American Journal of Emergency Medicine 38 (2020) 2014-2018

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Comparison of intravenous ibuprofen and paracetamol efficiency in Soft tissue injuries: A randomized, double-blind study

Sercan Yalcinli, MD ?, Guclu Selahattin Kiyan, Professor, Ozge Can, MD

Department of Emergency Medicine, Ege University, 35100 Izmir, Turkey

Introduction

Background

Soft tissue injuries are painful injuries of the musculoskeletal system that occur after sprains, strains, and muscle contusions. Pain control is required in the management of these patients. Providing adequate pain control can allow patients to return to their regular physical activ- ities by allowing early controlled mobilization, as well as patient comfort [1].

Paracetamol, Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are preferred in acute pain management. NSAIDs or paraceta- mol are used for mild and moderate pain, and combinations of these drugs with opioids are preferred in case of moderate and severe pain. However, due to the side effects associated with opioids and the risk of addiction, subTherapeutic doses and delayed treatments are applied. Therefore, patients may face the risk of oligoanalgesia [2].

The Visual analogue scale (VAS) and the Numeric rating scale (NRS) are often used to assess pain levels. It is reported that NRS and VAS are compatible with each other and can be used interchangeably in various studies [3,4]. Although it is reported that changing between 13 and 19 mm in VAS is sufficient to determine the minimum clinically important difference (MCID) for pain, it is stated that in assessing the re- duction in pain, clinically adequate pain control should be considered rather than MCID, and this was determined as a 30 mm decrease in VAS [5].

There are various studies in the literature on the use of paracetamol and NSAIDs separately or in combination in patients with soft tissue in- juries [6-10]. To the best of our knowledge, there is no randomized con- trolled trial in the emergency medicine literature, except in our study that compared intravenous (iv) ibuprofen and IV paracetamol, to pro- vide moderate to severe pain control within 60 min.

Objectives

The primary aim of the study is to compare pain levels at rest and in motion at 15th-30th-45th-60th minutes in patients who need analgesic and received iv ibuprofen or iv paracetamol due to the diagnosis of soft tissue injuries .

* Corresponding author at: Ege University Faculty of Medicine, Emergency Department, 35100 Izmir, Turkey.

E-mail address: [email protected] (S. Yalcinli).

The secondary aims of the study are to compare the need for additional Analgesic treatment in the 60th minute between groups and clinically adequate pain control efficacy according to NRS.

Hypotheses

Pain levels of the patients receiving ibuprofen due to soft tissue inju- ries are lower than patients receiving paracetamol at rest and in motion in the 15th-30th-45th-60th minutes. Patients receiving ibuprofen re- quire less rescue treatment, and clinically adequate pain control efficacy is more significant in those.

Materials and methods

Study design

The study was designed as a prospective, randomized, double-blind trial. It was held in the emergency department of a tertiary level univer- sity hospital, which has 200,000 patient admissions annually. Ege Uni- versity ethics committee and Republic of Turkey Ministry of Health approved the study and it was conducted according to the ethical rules of the 1975 Helsinki Declaration.

Study population and exclusion criteria

Patients between the ages of 18-64 years, who applied to the emer- gency department for acute (<= 24 h) trauma-related reasons, who were diagnosed with soft tissue injuries after the evaluation, who had >3/10 pain scores (moderate-severe pain) according to NRS and who re- quested analgesic treatment were included to the study. Patients who used analgesic 6 h before the admission, who had an allergy to the study medications or had a contraindication disease to use those medi- cations, who were pregnant or breastfeeding and patients who had con- sent and communication difficulties were not included in the study. Besides, patients with fractures, dislocations, lacerations were excluded from the study.

Randomization and blinding

A randomization scheme was created by the study coordinator in the computer environment with a simple random method, with drug group numbers equal. Case report forms were numbered. The prepara- tion of the corresponding drug in the randomization scheme according

https://doi.org/10.1016/j.ajem.2020.06.063

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to the case report form number of the patients included in the study was made by the assistant researcher, who did not measure patients’ pain scores. In this way, double blindness of the patient and the assistant re- searcher, who measured the effect of the drug, was achieved.

Interventions

Patients diagnosed with soft tissue injuries after an emergency phy- sician evaluation were included in the study. After obtaining consent from the patient, the drug [ibuprofen; (Intrafen 400 mg/ml 4 ml iv, GEN) or paracetamol (Paracerol 10 mg/ml 1000 Mg iv, POLIFARMA)] matching the number in the case report form, which was randomized, was prepared by the emergency physician researcher who did not per- form patient pain assessment. The label samples of the research prod- ucts were prepared in accordance with the “Good Manufacturing Practices Guide” so that the external appearance of the prepared drugs were completely similar. The drug content was applied blindingly to the patient and the emergency physician who will measure the treat- ment effect. Both drugs were applied within a 30-min infusion. Resting and moving pain scores of the patients at 0th-15th-30th-45th-60th mi- nutes were evaluated with NRS. Pain measurements during motion were evaluated by applying the same motion (flexion, extension, supi- nation, and pronation) in each time frame. Pain scores of the patients are grouped according to NRS as 1-3; mild, 4-6: moderate, 7-10; se- vere. Changes from 0 to 60 min from severe pain to moderate and mild pain, from moderate pain to mild pain were considered as recovery status and drug groups were compared. In patients’ resting or moving states at 60 min, the lack of 3 units or more reduction in their NRS and/or the patient’s request for additional analgesics were identified as the need for Rescue therapy. Paracetamol was administered to pa- tients receiving ibuprofen as rescue therapy, and ibuprofen was admin- istered to patients receiving paracetamol. In order to ensure patient safety during and after the drug infusion, vital monitoring (blood pres- sure, pulse, respiration, fever) of all patients were performed at the be- ginning, 30th and 60th minutes. At the end of the rescue treatments, vital signs of the patients were checked. Patients were observed for pos- sible drug side effects during their stay in the emergency department. The discharge treatment of the patients was left to the responsible emergency physician of the patient.

Outcomes

The 0th-15th-30th-45th-60th minutes at resting and in motion NRS scores of the patients were recorded. A decrease of 3 or more units in the NRS scores of the patients 60 min after the start of treatment was deter- mined as clinically adequate pain control efficacy [5]. In patients’ resting or moving states at 60 min, the lack of 3 units or more in their NRS scores and/or the patient’s request for additional analgesics were iden- tified as the need for Rescue drug requirement.

Sample size

In order to find the interaction between groups (ibuprofen or para- cetamol) and time (0th, 15th, 30th, 45th, and 60th minutes) statistically significant using ‘G. Power-3.1.9.2’ software for the study, 122 people, 61 of whom were in each group, were found sufficient under the re- peated measurement ANOVA test, with 80% power, ? = 0.05, f = 0.10, and the correlation between repeated measurements was 0.5. However, considering the possible loss observations, the sample size was determined as 172 patients.

Statistical method

In the study, numerical data were summarized with the help of IBM SPSS Statistics 25.0 (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) package program using mean, standard

deviation, median, minimum, maximum values and categorical data using frequency and rate values. In all analyzes, the level of significance was set at 0.05 (excluding interaction, p < .1). The suitability of variables to normal distribution was analyzed by analytical methods (Shapiro- Wilk test). Pain severity levels (mild-moderate-severe) in NRS at rest and in motion between groups between 0 and 60 min were examined with the help of the STATA 13 (StataCorp. 2013. Stata: Release 13. Statis- tical Software. College Station, TX: StataCorp LP. function: symmetry) software with the McNemarBowker test. Pearson chi-square test was used for group comparisons.

Since NRS scores were not normally distributed at rest and in mo- tion, time-dependent changes in drug groups were analyzed with the non-parametric method Brunner-Langer model (F1-LD-F1 design) with the help of R 3.5.2 software (R software, version 3.5.2, package: nparLD, R Foundation for Statistical Computing, Vienna, Austria;http:// r-project.org). As a result of the Brunner-Langer model, when the time-dependent change was not similar (interaction <0.1), the groups were compared at each point using the Mann-Whitney U test.

In case of rest and motion, clinically adequate pain control efficacy in NRS scores and patients’ Rescue medication demands were compared with the Pearson Chi-square test. The results are given together with the effect size values. The effect size was calculated according to the Cohen’s w coefficient w = ?(?^2/N) formula and was classified as w = 0.10 small, w = 0.30 medium and w = 0.50 large effect size.

Results

The 267 patients were evaluated for the study. The 95 patients were excluded because they did not meet the study criteria (Fig. 1: Patient Flow Chart). Demographic data, trauma mechanisms, and data of the af- fected body region of patients given ibuprofen (n:86) and paracetamol (n:86) are presented in Table 1. There was no difference between the groups in terms of age and gender (p = .949). It was determined that the male gender was higher in both groups. There was no difference be- tween the groups in terms of Trauma mechanisms (p = .665). Traumatic contusions were the most common reason for admission in both groups. body parts of the patients exposed to trauma were similar in both groups (p = .371). Lower extremity injuries were the most common reason for admission in both groups.

In the resting pain scores, a decrease in pain levels was observed in both drug groups for 60 min (p < .001 for both), and the pain reduction was higher in the ibuprofen group (p = 0,005). This difference emerged at the 30th minute (Table 2). When in motion, pain scores were exam- ined, it was found that the reduction rates in pain were statistically sig- nificant in both groups (p < 0,001 for both). But there was no statistically significant difference between the drugs at all times in mo- tion pain scores (p = 0,088) (Table 2). Motion pain score reduction was similar in both drugs. Pain changes between drug groups at rest and at motion are presented in Figs. 2 and 3.

When the pain levels of the patients were divided into mild (0-3), moderate (4-6), and severe (7-10) pain groups according to NRS and when the rest and motion pain changes of the drugs were evaluated; it was determined that pain levels in the paracetamol and ibuprofen groups showed statistically significant changes in the direction of healing (from severe to moderate, from moderate to mild) (p < .0001). At rest, 53.4% (n:46) of patients in the paracetamol group and 73.3% (n:63) of patients in the ibuprofen group were found to have a change from moderate pain levels to mild pain levels during 0-60 min. In the motion, 37.2% (n:32) of patients in the paracetamol group and 37% (n:32) of patients in the ibuprofen group were found to have a change from severe pain levels to mild pain levels during 0-60 min. Improve- ment status at rest among drug groups was statistically significantly higher in the ibuprofen group (for ibuprofen:96.5%, for paraceta- mol:83.7%) (p:0.005, Pearson Chi-Square). No statistically significant difference was observed between the drug groups in terms of improve-

ment in motion (p:0.321, Pearson Chi-Square) (Table 3).

Assessed for Eligibility :267

Excluded Patients: Unable to consent: 40 Refused iv treatment: 28

Contraindications for drugs: 10 Fractures: 7

Communication difficulties: 4 Admissions after>24 hours: 3 Analgesia before admission: 2

Lactation: 1

Randomisation: 172

Allocated to paracetamol, n: 86

received 1000 mg iv paracetamol

Allocation

Allocated to ibuprofen, n:86

received 400 mg iv ibuprofen

Lost to follow-up, n:0

Discontinued intervention, n:0

Follow-up

Lost to follow-up, n:0

Discontinued intervention, n:0

Analysed n: 86

Analysis

Analysed n: 86

Fig. 1. Patient flow chart.

Table 1

Demographic data of patients.

	Paracetamol n:86	Ibuprofen n:86	Total n:172	p
Age Mean +- SD	32.8 +- 11.4	32.4 +- 10	32.6 +- 10.8	0.949
(Minimum-Maximum) Gender	(18-61)	(18-60)	(18-61)
Female	33 (38)	25 (29)	58 (34)

NRS score, it was determined that patients in the ibuprofen group needed less rescue medication (p = 0,005). It was also determined that patients demanding rescue drugs were less in the ibuprofen group (p = 0,030). In these three statistical evaluations, the effect size was found to be small (w < 0.30).

Discussion

Male	53 (62)	61 (71)	114 (66)	0.197	As far as we know, for the first time in the literature, we evaluated
Mechanism of Trauma					the pain-relieving efficacy both at rest and in motion by giving iv ibu-

Sprain	23 (27)	26 (30)	49 (28)
Strain	24 (28)	19 (22)	43 (25)
Contusion Site of Injury	39 (45)	41 (48)	80 (47)	0.665
Upper Extremity	17 (20)	14 (16)	31 (18)	0.371
Lower Extremity	41 (48)	51 (59)	92 (54)
Trunk	21 (24)	14 (16)	35 (20)
Pelvic	6 (7)	4 (5)	10 (6)
Neck	1 (1)	3 (4)	4 (2)

Data regarding patients’ need for clinically adequate pain control ef- ficacy and rescue drug are presented in Table 4. Accordingly, patients in the ibuprofen group had more clinically adequate pain control efficacy at rest (p = .001) and in motion (p = .012). Again, according to the

profen 400 mg or iv paracetamol 1000 mg to patients with soft tissue in- juries who admitted to the emergency department for moderate to severe pain. As a result of the study, we found that iv ibuprofen and iv paracetamol provided a significant reduction in pain within the first

60 min, iv ibuprofen provided more pain reduction at rest after

30 min than iv paracetamol. Also, clinically adequate pain control effi- cacy was greater in the ibuprofen group for both at rest and in motion, and rescue medication need was less in those patients.

It seems that there is no strong consensus on which drug is superior to each other in studies related to opioids, NSAIDs and paracetamol use for pain control due to soft tissue injuries [1,6,11]. There are studies showing that when used paracetamol alone or in combination with NSAIDs, similar Analgesic efficacy was achieved [7,9,10] [12-15],.

Table 2

NRS Scores of patients at rest and in motion.

	Rest Pain Scores Time (Minutes)		Paracetamol n:86 Mean	S.D.	Median		Min.	Maks.			Ibuprofen n:86 Mean	S.D.	Median	Min.	Maks.	p?
	0th		5.8	1.7	6.0		4.0	10.0			5.5	1.4	5.0	4.0	10.0	0.170
	15th		4.3	2.2	4.0		0	9.0			3.8	2.1	4.0	0	10.0	0.123
	30th		3.3	2.4	3.0		0	8.0			2.4	2.1	2.0	0	10.0	0.008
	45th		2.7	2.3	2.0		0	8.0			1.7	1.7	1.5	0	7.0	0.011
	60th P??		2.3 Group: 0.059	2.3	2.0		0	8.0			1.3	1.5	1.0	0	6.0	0.005
			Time: <0.001
			Interaction: 0.005
Motion Pain Scores			Paracerol									Ibuprofen
			n:86									n:86
			Mean		S.D.	Median	Min.		Maks.			Mean	S.D.	Median	Min.	Maks.
0th			8.3		1.5	8.3	5.0		10.0			8.1	1.6	8.0	4.0	10.0
15th			6.7		1.9	7.0	2.0		10.0			6.5	2.3	6.0	0	10.0
30th			5.6		2.3	6.0	0		10.0			5.1	2.5	5.0	0	10.0
45th			4.7		2.5	5.0	0		10.0			4.1	2.3	4.0	0	10.0
60th P??			4.4 Group:0.088		2.6	4.3	0		10.0			3.6	2.3	3.0	0	10.0
			Time:<0.001

* Mann Whitney U Testi.

?? Brunner-Langer model.

Interaction:0.313

Although opioids are used for rapid and strong analgesic efficacy in pa- tients with moderate to severe pain, the side effects of these drugs pose a major problem [11]. It is also reported that the use of opioids with paracetamol and other NSAIDs does not provide additional benefits in the acute period in analgesic effect, and opioids increase the frequency of side effects [8]. This situation reveals the need for medication that can be used safely in patients with moderate to severe pain. As far as we know, our study is the first emergency medicine study to emphasize that iv ibuprofen and iv paracetamol are effective in patients with soft tissue injuries to control acute moderate and severe pain and because of their reliable side effect profile these drugs may be used safely in this patient group in the emergency medicine. It is also important to emphasize that iv ibuprofen provides faster and more effective analge- sia than iv paracetamol.

Ibuprofen is an FDA approved drug for Intravenous use in 2009. In pharmacokinetic studies, it is reported that the administration of the 400 mg iv form with an infusion of 30 min reaches an earlier plasma maximum concentration in comparison with the oral tablet [16]. It is stated that there is no difference in creating an analgesic effect for pain in 60 min between orally administered 400, 600, 800 mg tablets [17]. It is also stated that in a clinical condition characterized by severe pain such as renal colic, the pain-relieving activity of iv ibuprofen starts

earlier and is two times more effective compared to ketorolac, which is also an NSAID [18]. In the study by Bondarsky et al., comparing 800 mg ibuprofen, 1 g paracetamol and their combinations, it was found that there was no difference between groups in terms of pain control within 0-60 min and need for rescue medicine. However, when the data of the study are evaluated, it is observed that the clinically adequate pain con- trol efficacy is not reached in the 60th minute (decrease 30 mm in GAS) [10]. In the study by Gong et al., it has been reported that the combina- tion of oral paracetamol, ibuprofen, codeine does not provide an advan- tage in providing analgesic activity within 60 min at rest and in motion compared to oral paracetamol alone [8]. However, in this study, it was observed that the NRS scores of the patients in both groups decreased less than three units after 60 min, and clinically adequate pain relief ef- ficacy could not be achieved. In our study, we observed that paraceta- mol and ibuprofen administered iv had a faster effect and more efficacy than orally administered studies and that clinically adequate analgesic effect was achieved in 93% of patients receiving ibuprofen 400 mg. At the same time, there were no acute side effects for both drugs with a 30-min infusion rate. In the future, considering the data re- garding that iv ibuprofen can be given as a 5-7 min infusion [19], we think that studies on achieving analgesic efficacy and evaluating the side effect profile can be done in patients with moderate to severe pain.

Fig. 2. Change of NRS scores at rest. Fig. 3. Change of NRS scores in motion.

Table 3

Pain level changes of drug groups at rest and in motion in 0-60 minutes.

				Rest T60
	Paracetamol		Mild	Moderate	Severe	Total	p
	Rest T0 Mild		0	0	0	0	0.0000
	Moderate		46 (53)	9 (11)	0	55 (64)
	Severe		17 (20)	9 (11)	5 (5)	31 (36)
	Total		63 (73)	18 (22)	5 (5)	86 (100)
				Motion T60
	Paracetamol		Mild	Moderate	Severe	Total	p
	Motion T0 Mild		0	0	0	0	0.0000
	Moderate		6 (7)	3 (4)	0	9 (11)
	Severe		30 (35)	32 (37)	15 (17)	77 (89)
	Total		36 (42)	35 (41)	15 (17)	86 (100)
				Rest T60
	Ibuprofen		Mild	Moderate	Severe	Total	p
Rest T0		Mild	0	0	0	0	0.0000
		Moderate	63 (73)	3 (4)	0	66 (77)
		Severe	13 (15)	7 (8)	0	20 (23)
		Total	76 (88)	10 (12)	0	86 (100)
				Motion T60
	Ibuprofen		Mild	Moderate	Severe	Total	P
	Motion T0	Mild	0	0	0	0	0.0000
		Moderate	14 (16)	2 (3)	0	16 (19)
		Severe	32 (37)	27 (31)	11 (13)	70 (81)
		Total	46 (53)	29 (34)	11 (13)	86 (100)

Table 4

Comparison of clinical adequate pain control efficacy and rescue drug need among drug groups.

ibuprofen than paracetamol, and there is less demand for rescue medi- cation. No side effects were found in the acute iv use of both drugs.

Funding

This article was supported by Ege University Scientific Research Pro- jects Coordination (Project Code: 16-TIP-091).

Declaration of Competing Interest

Authors report no conflict of interest.

Acknowledgements

We thank all of our patients who agreed to participate in our re- search, and also Timur Kose and Semiha Ozgul for their contributions to the statistical analysis. We also express our gratitude to the emer- gency medicine residents; Ece Yilmaz, Emre Ustsoy, Cemile Yurtseven, Gulten Kara, Mevlut Ozden, Eylul Destina Firat, Zisan Andizoglu for their support during the data collection.

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