a b s t r a c t

Introduction: Non-traumatic back pain constitutes roughly 5% of the admissions to emergency departments. This study seeks to compare the efficacy of intravenously administered paracetamol, dexketoprofen, and ibuprofen in patients with non-traumatic Acute low back pain.

Methods: This study was designed as a randomized, double-blinded investigation and carried out at a tertiary hospital. 210 eligible patients without trauma who presented with low back pain were recruited for the study and randomized into paracetamol (n = 71), dexketoprofen (n = 70), and ibuprofen (n = 69) groups. The mea- surements at 0, 15, 30 and 60 min were noted down by using a 100 mm VAS, and the relevant comparisons were made.

Results: The VAS scores at 0 and 60 min in the paracetamol, dexketoprofen, and ibuprofen groups decreased on average by 40 mm, 42 mm, and 43 mm, respectively. The baseline and final pain scores of each drug group dif- fered significantly (p < 0.05), though the between-group analysis revealed no significant difference (p > 0.05). Conclusion: Given the obtained data, we did not note a significant difference between Intravenous paracetamol, dexketoprofen and ibuprofen with respect to pain efficacy in non-traumatic acute low back pain. Based on the patients’ clinical conditions and histories, we concluded that the choice of medication might not change the ef- ficacy of the treatment and patient comfort.

(C) 2022

1. Introduction

Lower back is used to describe the area of the back that covers the lumbar vertebral part. Over 84% of people tend to complain about low back pain at some point over the course of their lives [1]. This type of pain is commonly induced by mechanical factors concerning musculo- skeletal system. Its frequency rises after the age of 40, and this pain is observed more often in women than in men [2]. Patients with acute low back pain (<6 weeks) often recover and return to their normal lives thanks to medication and supportive therapy [3].

Analgesic drugs effectively enhance the Comfort level of patients with this pain and help to maintain their vital functions due to their Analgesic efficacy. For this purpose, the analgesic drugs commonly prescribed and administered for the treatment of low back pain are oral, parenteral and Topical NSAIDs (nonsteroidal anti-inflammatory drugs), paracetamol, tramadol, and opioids [4]. Drugs containing these

* Corresponding author at: Department of Emergency Medicine, Pamukkale University Hospital, Pamukkale University of Medical Sciences, 20070, Kinikli/Denizli, Turkey.

E-mail address: [email protected] (I. Turkcuer).

agents are often administered parenterally in the treatment of non- traumatic acute low back pain in the context of emergency practice. The relevant literature reveals the lack of sufficient investigation com- paring the efficacy of the aforementioned drugs at the same time.

Our study essentially seeks to perform a comparative evaluation of the efficacy of paracetamol, dexketoprofen, and ibuprofen in the treat- ment of non-traumatic acute low back pain.

1. Methods
   1. Study type

This equivalence study was initiated after granting the approval from XXXXXX University (PAU) Non-Interventional Clinical Trials Ethics Committee. Our study was registered and approved by the American clinical trial registry (NCT04609254 at https://clinicaltrials.gov).

• 1. Study population

Our Healthcare facility has 835 bED capacity and 1,500,000 outpa- tient admissions per year, while the ED has 45 bed capacity, with the

https://doi.org/10.1016/j.ajem.2022.04.017

0735-6757/(C) 2022

annual patient load amounting to nearly 120,000 patients. We evalu- ated the patients who presented with complaints of acute low back pain and did not suffer any trauma during the study in PAU emergency medicine clinic. The eligible patients were recruited in accordance with the pre-specified inclusion and exclusion criteria.

• 1. Subject selection

Inclusion Criteria: We selected the eligible patients over 18 and under 65 who presented to our emergency department with complaints of non-traumatic acute low back pain, had VAS (visual analog scale) score > 50 mm, and gave their informed consent to participate in the study.

Exclusion Criteria: The patients with the following conditions were excluded from the study:

• • • severe liver, kidney, pulmonary and cardiac heart failure.
    • pregnancy and breast-feeding.
    • receiving analgesics in the last 6 h.
    • being at a childbearing age and taking contraceptives.
    • Neurological deficits.
    • cardiac-induced chest pain.
    • chronic pain.
    • reflected and neoplastic pain.
    • pre-existing ibuprofen-, dexketoprofen- and paracetamol-induced gastrointestinal bleeding and perforation.
    • history of being allergic to study drugs (ibuprofen, paracetamol, and dexketoprofen).
    • illiteracy and eye-sight problems.
    • marking the severity of pain as 50 mm or less on the 100 mm VAS scale.
  1. Research protocol
     • The study staff to perform the research protocol (emergency physi- cians and nurses) were trained prior to the study.
     • If the participants matched the inclusion criteria, their written in- formed consent was obtained along with their baseline values, includ- ing initial severity ratings of non-traumatic acute low back pain on the Visual analog scale .
     • All the eligible patients were randomized into one of the following three groups:

Group 1: 71 patients were administered with 1000 mg of IV paracet- amol (Parol 1000 mg vial – Atabay Chemistry – Istanbul).

Group 2: 70 patients were given 50 mg of IV dexketoprofen (Arveles 50 mg ampoule – Menarini – Istanbul).

Group 3: 69 patients were provided with 400 mg of IV ibuprofen (Intrafen 400 mg vial – Gen – Istanbul).

• • • The drug packs prepared in 150 ml serum physiology were num- bered by an independent nurse who was not involved in the study.
    • The study drugs were administered in accordance with the computer-generated random number sequence to devise patient alloca- tions.
    • The allocation list was kept by the emergency nurse. The patients followed the medication schemes of paracetamol, dexketoprofen, and ibuprofen according to their random allocations.
    • After the enrollment procedures and the recording of the baseline information, the numbered study drug pack was obtained and adminis- tered intravenously during 15 min.
    • During the intervention, the participants were monitored by an ox- ygen saturation (SpO2) monitor, an automatic sphygmomanometer (blood pressure), and a rhythm monitor (heart rate and rhythms).
    • One researcher blinded to the patient allocation observed the whole procedure and noted down the scores for non-traumatic acute low back pain.
    • The patients in the three groups received three types of medication in a similar fashion. The scores for non-traumatic acute low back pain

were measured between 1 and 100 on the VAS at 0, 15, 30 and 60 min. During the study, pulse rate, systolic blood pressure, diastolic blood pressure and respiration rate were recorded at baseline (0), 15, 30, and 60 min. The procedure was terminated at 60 min. We planned fentanyl 1 ug/kg IV administration for the patients with VAS score 50 mm and above after 60 min for the rescue treatment.

• 1. Data analysis

We performed a Power calculation to identify the minimum number of participants required to determine whether the study drugs produce a significant effect. Considering a significance value of p < 0.05 and 90% power, we calculated that at least 59 participants were needed for each group. The collected data were computerized and analyzed with SPSS v25.0 Windows (SPSS Inc., Chicago IL, USA). The descriptive criterion, namely the VAS score, was presented as mean score and percentage breakdown. The mean scores were provided as “mean +- standard devi- ation”. The normality distribution of the data was checked using the Kolmogorov-Smirnov test. For parametric test assumptions, ANOVA was performed in comparing independent group means. A Kruskal- Wallis analysis was conducted if parametric assumptions were violated. A Friedman test was carried out to compare the groups in statistically repetitive measurements (VAS). The significance level was set at p < 0.05 for all analyses.

1. Results

During the study period, roughly 154,000 patients presented to the PAU adult emergency department. Of 2134 patients (1.3%) initially screened for complaints of low back pain, 210 eligible patients (0.1%) were included in the study and randomized to receive the three study drugs (Fig. 1).

Of the 210 patients recruited into the study, 112 (53.3%) were fe- male and 98 (46.7%) were male. No significant difference was evident between the groups in relation to baseline Vital parameters (Table 1). Considering the VAS scores of all three groups, the study drugs proved effective for all groups, providing a significant decrease in the VAS scores (p < 0.05) (Table 2, Fig. 2).

As far as the between-group differences in ?VAS scores are con- cerned, we did not detect a significant difference for all groups at all time intervals. When we analyzed 0-60 min VAS scores for all the drug groups, paracetamol (p < 0.001), dexketoprofen (p < 0.001), and ibuprofen (p < 0.001) drugs turned out to reduce VAS scores signifi- cantly and provide significantly better analgesic efficacy (Table 3). Dur- ing the conduct of our study, no need arose for Rescue therapy, nor were any side effects observed in all three drug groups.

1. Discussion

The most clinically relevant finding obtained from our dataset is the presence of the significant decrease in the VAS scores for all three drugs whose analgesic efficacy was assessed at 0, 15, 30 and 60 min. Another obvious finding to emerge from our analysis is that these drugs provide sufficient and similar pain-relief effect in comparison with each other.

Low back pain stands as one of the leading causes of disability world- wide and requires a quick and effective treatment. Some clinical research and meta-analyses on acute low back pain do not document any superiority of paracetamol over placebo [5,6]. A meta-analysis published in 2018 suggests that a majority of the existing guidelines recommend NSAIDs for the treatment of this pain, yet this analysis also reveals that the recommendation for the administration of paracet- amol is addressed in about half of these guidelines [7]. An overview review describes ibuprofen and paracetamol as drugs with proven analgesic effects but conclusively demonstrates that the former is com- monly superior to the latter when administered at standard doses in a variety of painful conditions [8]. This overview also highlights the lack

Fig. 1. Flow Chart.

of convincing empirical evidence that paracetamol provides clinically significant efficacy in a range of painful conditions. On the other hand, our prospective trial is a proof that paracetamol is as effective as NSAIDs (dexketoprofen and ibuprofen) in alleviating low back pain, which is one of the acute painful conditions.

The reduction of high mortality rates caused by the misuse and abuse of strong opioids is another important element in relieving acute pain. The review by Berthelot et al. on using strong opioids, para- cetamol, and NSAIDs in non-cancer Musculoskeletal pain concludes that the analgesic efficacy of potent opioids did not differ from that of

Table 1

The baseline vital parameters of the study groups.

Baseline Parameters	Paracetamol (n:71)	Dexketoprofen (n:70)	Ibuprofen (n:69)	P*
Systolic blood pressure (mean +- SD)	124,64 +- 11,03	124,72 +- 12,07	124,11 +- 11,16	0,94
Diastolic blood pressure (mean +- SD)	79,28 +- 7,55	78,14 +- 8,74	77,46 +- 9,11	0,44
Pulse rate (mean +- SD)	78,87 +- 9,35	80,34 +- 8,62	78,52 +- 9,18	0,45
Respiratory rate (mean +- SD)	13,98 +- 2,2	13,64 +- 1,64	14,24 +- 1,65	0,16
p*: derived from the ANOVA analysis.

Table 2

Comparison of VAS scores at 0, 15, 30, and 60 min between paracetamol, dexketoprofen and ibuprofen.

	Paracetamol (n = 71)	Dexketoprofen (n = 70)	Ibuprofen (n = 69)	p
VAS 0 min.	84.64 +- 9.68	78.84 +- 12.91	85.39 +- 10.61	0,002
VAS 15 min.	70.35 +- 10.22	63.01 +- 11.03	70.28 +- 14.84	0,001
VAS 30 min.	56.76 +- 17.03	50.88 +- 12.56	57.60 +- 19.30	0,008
VAS 60 min.	44.70 +- 19.93	36.35 +- 15.89	42.46 +- 25.27	0,049

p: derived from Independent Samples Kruskal-Wallis analysis.

Fig. 2. Comparison of VAS scores at 0, 15, 30, and 60 min between paracetamol, dexketoprofen and ibuprofen.

paracetamol, and that they turned out to produce weaker effects than NSAIDs [9]. Some published clinical studies recommend the administra- tion of weak opioids in cases with no response to NSAIDs and other treatments. More than half of the guidelines likewise recommend the use of opioids during the pain process in the alleviation of acute low back pain [7]. When it comes to our study, non-opioid drugs proved suf- ficient and effective in relieving acute low back pain. This finding can be considered clinically valuable in terms of minimizing opioid use in the treatment of low back pain, which is one of the acute pains.

Some randomized clinical trials report that NSAID monotherapy is likely to produce the same effect as the Combination therapy in terms of re-admission and functional outcomes [10,11]. Another multicenter study finds more prolonged and faster onset of action of

ibuprofen + paracetamol combination than ibuprofen monotherapy in the treatment of acute low back pain [12]. The same study also under- scores equally positive outcomes of the combined therapy on mobility, functional ability, and tolerability. Similarly, our trial administered monotherapy and noted effective analgesic outcomes, as indicated by VAS scores, thereby minimizing the risk of side effects that may arise due to multi-drug therapy.

McCarberg’s review reveals that orally-administered paracetamol does not prove so effective as NSAIDs in alleviating acute low back pain [13]. Likewise, a double-blind trial by Williams et al. does not provide sufficient clinical evidence on the efficacy of oral paracetamol treatment in acute low back pain [14]. Another double-blind study com- paring the efficacy of IV morphine, paracetamol and dexketoprofen in acute Mechanical low back pain concludes that all three drugs achieves sufficient pain relief, and that paracetamol provides similar analgesic effect to morphine [15]. It is also stressed that more Rescue drugs were required in the paracetamol and dexketoprofen groups. In contrast, our findings demonstrate that 1000 mg IV paracetamol can prove as ef- fective as IV NSAIDs by producing efficacious analgesia and eliminating the need for rescue therapy.

Even though the data we obtained bear some similarities to the re- sults documented by other studies, we provide the researchers and practitioners with evidence-informed opinion on the effectiveness of paracetamol. In this respect, the lack of relevant research on comparing the IV treatment of these three drugs can serve as a precursor to future studies. Another important aspect deserving attention is that this trial was performed on a larger patient population relative to other studies.

1. Limitations

The major limitations of the present study can be listed as the lack of a placebo group, insufficient follow-up span with respect to

Table 3

Comparison of VAS scores at 0, 15, 30, and 60 min with ?VAS between paracetamol, dexketoprofen and ibuprofen.

	Paracetamol (n = 71)	Dexketoprofen (n = 70)	Ibuprofen (n = 69)	P
?VAS 15 min – 0 min	14.29 +- 7.47	15.82 +- 8.41	15.10 +- 9.53	0,565
?VAS 30 min – 0 min	27.88 +- 16.09	27.95 +- 14.04	27.78 +- 16.22	0,998
?VAS 60 min – 0 min	39.94 +- 18.63	42.48 +- 19.69	42.92 +- 24.32	0,662
?VAS 30 min – 15 min	13.59 +- 10.18	12.12 +- 7.86	12.68 +- 8.85	0,624
?VAS 60 min – 15 min	25.64 +- 14.05	26.65 +- 14.91	27.82 +- 19.78	0,735
?VAS 60 min – 30 min	12.05 +- 10.20	14.52 +- 9.79	15.14 +- 14.16	0,246
p*	<0,001	<0,001	<0,001

p*: derived from Friedman test; P: derived from ANOVA analysis.

functional capacity and mobilization, and failure to evaluate recurrent admissions. In addition, the difference in baseline VAS scores between dexketoprofen and paracetamol and between dexketoprofen and ibuprofen is another limitation of our study.

1. Conclusion

All the study drugs (paracetamol, dexketoprofen, ibuprofen) mani- fested similar pain relief in patients without trauma who presented to the emergency service with acute low back pain. Moreover, these drugs did not prove any clinical superiority over one another. Consider- ing our patient cohort, all three drugs were established to be sufficient in terms of analgesic efficacy, and no need arose for additional treat- ment in any drug group. The preference for drugs made in relation to the additional clinical conditions and previous histories of the patients are not likely to change the effectiveness of the treatment.

Author contribution statement

1-Study concept and design: C.D., A.Y., and I.T. 2-Acquisition of data: C.D., A.Y., A.K., M.U., M.O., M.S., A.O., and I.T. 3-Analysis and interpreta- tion of data: C.D., A.Y., and I.T. 4-Drafting of the manuscript: C.D., A.Y., M.U., and I.T. 5-Critical revision of the manuscript for important intellec- tual content: C.D., A.Y., and I.T. 6-Statistical analysis: C.D., A.K. and I.T. 7-Administrative, technical and material support: C.D., A.Y., A.K., M.U., M.O., M.S., A.O., and I.T. 8-Study supervision: C.D., A.Y., M.O., M.S., A.O.,

and I.T.

CRediT authorship contribution statement

Cansu Dogan: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Atakan Yilmaz: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Mert Ozen: Funding acquisition, Project administration, Supervision. Murat Seyit: Supervision, Project administration, Funding acquisition. Alten Oskay: Funding acquisition, Project administration, Supervision. Aykut Kemanci: Project administration, Funding acquisition, Formal analysis. Mehmet Uluturk: Funding acquisition, Project administration, Writing – original draft. Ibrahim Turkcuer: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software,

Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no conflicts of interests.

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