FormalPara Key Summary Points

Why carry out this study?

Musculoskeletal disorders are a leading cause of disability, and effective pain management is crucial for a speedy recovery, and it is necessary to implement a strategy like multimodal analgesia to improve acute and chronic pain.

Efficient multimodal analgesia is achieved through the combination of medications with different mechanisms of action, resulting in superior pain relief with reduced doses and enhanced tolerability.

The analgesic combination with tramadol and non-opioid analgesics agents favors the opioid-sparing effect, which means achieving similar pain control with lower opioids doses, along with a lower incidence of opioid-related side effects.

What was learned from this study?

The present study provides the first evidence of the analgesic efficacy (pain and disability) and security (adverse events) of fixed-dose combination (FDC) etoricoxib/tramadol in acute low back pain (LBP) management.

This study provides strong evidence for using etoricoxib/tramadol to manage acute LBP effectively. This combination delivers the same therapeutic effect as standard treatment but with a lower daily dose of tramadol (50 mg vs. 112.5 mg/day) due to their remarkable synergy.

Introduction

The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage [1]. Pain is the leading cause of medical evaluation, mainly due to acute pain; defined as the physiological response to an adverse stimulus (mechanical, thermal, or chemical) associated with surgery, trauma, or critical illness [2]. According to the data reported in the Global Burden of Disease Study, musculoskeletal disorders are considered the second cause of disability in the world (causing 16% of the years lived with disability), it was also identified that low back pain continues as the most common reason for disability since the first measurements were made in 1990 [3]. By 2020, there will be 619 million people affected by this condition worldwide, and it is estimated that by 2050 this number will increase to more than 800 million cases [4]. Treatment in patients with acute low back pain (LBP) should be given sparingly, aimed at pain control and advance to the current functional status. Pain management continues to be a subject of a great dilemma because it has a multifactorial origin; its control can become difficult through a single drug prescription. One of the most employ strategies for acute and chronic pain management is multimodal analgesia which is defined as the prescription of more than one pharmacological class of analgesic medication targeting different receptors along the pain pathway with the goal of improving therapeutic effect while reducing individual class-related side effects [5, 6].

Based on a literature review, oral analgesic combinations with different mechanisms of action are recommended because they offer additional clinical benefits for the patients. Employing combination therapies results in improved tolerability and synergistically increased analgesic effects in certain conditions, thus enhancing efficacy and safety. Another reported advantage of multimodal analgesia is the possible decrease in the transition from acute pain to chronic pain [5, 7].

Several studies recommend using a combination of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) with opioids to manage moderate to severe acute pain. This combination offers additional pain relief and fewer undesirable side effects. The DANTE Study evaluated a fixed-dose (FDC) combination of cyclo-oxygenase (COX) inhibitor and opioid receptor agonist, specifically the combination tramadol/dexketoprofen. This combination shows promise as a multimodal analgesic option due to its efficacy in providing pain relief for both somatic and visceral pain in surgical models [8].

Etoricoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used for pain relief secondary to several musculoskeletal diseases, such as osteoarthritis and rheumatoid arthritis. The main characteristic of these agents is that they interrupt the synthesis of prostaglandins by inhibiting cyclooxygenase (COX). In this way, they can reduce pain and inflammation, producing an analgesic effect [9]. It has been reported to have similar efficacy and a superior safety profile in comparison to traditional NSAIDs (including naproxen, diclofenac, and ibuprofen), as well as being a long-acting drug due to its elimination half-life (> 22 h) allowing once-daily administration [10]. In a phase III study, etoricoxib 90 mg, taken once daily for 3 months, showed remarkable efficacy in treating acute low back pain. Notably, within the first 4 weeks of treatment, there was a substantial 23.2 to 23.4-mm reduction in pain intensity on the Visual Analogue Scale (VAS). Furthermore, compared to the placebo, the treatment resulted in statistically significant improvements in disability, function, and overall quality of life for the patients [11].

Tramadol is an atypical synthetic opioid analgesic owing to its opioidergic, noradrenergic and serotonergic effects, with a significant affinity towards µ receptors. Its principal pharmacological action is to relieve pain, producing satisfactory analgesia, and it is currently approved for the treatment of moderate to severe pain, its efficacy and safety have been evaluated through several clinical studies, including post-operative and cancer-related pain, among others [12].

In order to relieve moderate to severe pain, in clinical practice, the prescription of tramadol is often indicated in combination with non-opioid analgesics, their combination shows a faster onset effect after intake and prolonged duration. As mentioned earlier this strategy for pain management is consistent with the implementation of multimodal analgesia, a term proposed as a clinical approach in the 1990s, which has become widespread in clinical practice. Among its advantages, multimodal analgesia with tramadol and non-opioid analgesics agents favors the opioid-sparing effect, which means achieving similar pain control with lower opioids doses, along with a lower incidence of opioid-related side effects, such as nausea, vomiting, sedation, and pruritus. Other benefits associated with this therapy include an inferior risk of opioid misuse and abuse, thus minimizing the undesirable effects of opioids by facilitating the use of the lowest effective dose of opioids. In this sense, the combination of an oral opioid drug (such tramadol) and a non-opioid drug (such etoricoxib), in a FDC formula, offers an alternative when seeking to maximize therapeutic effect while minimizing side effects [13].

The FDC of tramadol/paracetamol has been extensively evaluated and compared with other combinations for the management of moderate to severe acute pain [14]. In acute LBP, tramadol (37.5 mg)/paracetamol (325 mg) is generally prescribed with a maximum consumption of ten doses per day [15].

The study hypothesis was that the combined analgesic action of a selective COX-2 inhibitor and a synthetic opioid in a new FDC therapy of etoricoxib (90 mg) and tramadol (50 mg) administered once daily could be a beneficial therapeutic option for reducing acute low back pain compared to standard treatment.

Methods

This was a phase IIIb, two-arm, prospective, longitudinal, randomized, controlled, open-label, 7-day treatment, and multicenter clinical trial conducted at three clinical sites in Mexico. The study was performed, with the main objective of evaluating the efficacy and safety of two FDCs of immediate release: etoricoxib 90 mg/tramadol 50 mg (one packet granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) in adult patients with acute low back pain. To evaluate the efficacy of these interventions changes in pain intensity (Visual Analog Scale [VAS] score) and disability (Oswestry Disability Index [ODI] and Roland–Morris Disability Questionnaire [RMDQ]) were evaluated. The safety analysis included biochemical markers, vital signs, and adverse events (AEs) records.

The study was open due to the challenges of blinding caused by differences in pharmaceutical forms, frequency of administration, dosage, and consumption instructions for both medications. We used simple randomization via the www.randomizer.org platform, balanced by treatment. Sealed randomization envelopes were used for each kit. The sponsor provided the randomized medications, and the study treatments were distributed at each visit by personnel delegated by the principal investigator.

The doses of both etoricoxib and tramadol administered were standard doses used in routine medical practice. These doses have been shown to maintain efficacy and safety when used as monotherapy.

Patients

Patients between 18 and 60 years of age, both genders, with the diagnosis of acute LBP, reported as moderate to severe intensity (VAS ≥ 4 cm) were included. Acute LBP is diagnosed based on clinical criteria. It is characterized by pain in the back from the lowest rib to the gluteal fold, with or without radiation to the legs. This pain may occur as a first-time episode or as a recurrence at least 6 months after a prior episode, and it typically lasts no more than 6 weeks. The study included patients who experienced sudden and intense LBP due to mechanical causes (such as forced movements or prolonged bad posture) or non-specific causes (meaning the patient had lower back pain without a reliably identifiable specific underlying condition). Patients with inflammatory LBP were not included in the study.

The main exclusion criteria were previous treatment with opioids and/or NSAIDs reported in the medical record in the last 72 h at study entry, intake of monoamine oxidase inhibitors (MAOIs) consumption within the last 2 weeks, and history of gastrointestinal disorders (for example; gastric ulcer, Crohn's disease, and ulcerative colitis), pregnant or breastfeeding women. Patients were evaluated from the September to the December 2021.

Patients were randomized into two treatment groups, A: received etoricoxib 90 mg/tramadol 50 mg granulate FDC (diluted in 100 ml of water) QD and B: received paracetamol 325 mg/tramadol 37.5 mg FDC, one tablet TID. Patients were assessed at baseline and subsequently on days 3, 5, and 7 of treatment; pain intensity was the primary efficacy outcome and it was measured with VAS, making it the preferred assessment method in the morning. The VAS (ranges from 0 [absence of pain] to 10 cm [worst imaginable pain]) is probably the most sensitive single-item measure for clinical pain research [16]. Treatment responders versus no responders were also evaluated; a responder definition has been determined from the clinically meaningful change as an absolute reduction ≥ 30% on the VAS. If the patient does not experience pain improvement with the study drug 24 h after the first dose, the patient may receive 800 mg of ibuprofen every 8 h.

Secondary efficacy variables included the assessment of disability in patients with acute LBP through ODI and RMDQ questionnaires, which were performed at baseline and 7th day. ODI is one of the most commonly used self-applied questionnaires that measure the limitations in daily activities in the presence of pain in the lumbar region. It consists of ten questions with six possible answers considering the intensity of the pain and basic activities from daily life [17]. Moreover, RMDQ focused on pain and aspects of daily life activities. It is a self-applied tool, the values range between 0 (no disability) and 24 (maximum disability) and allows categorize according to the relevance of the score obtained where the optimal variation threshold is 3 and 4 points, this instrument was evaluated on the same occasions as the ODI [18]. The Spanish version of the ODI was approval to use by Mapi Research Trust, Lyon, France, (https://eprovide.mapi-trust.org) [19,20,21,22,23,24]. In addition, safety profile was evaluated by reporting AEs, vital signs, and changes in biochemical and hematological laboratory parameters. AEs were evaluated according to severity, causality, seriousness, expectedness, classified according to the corresponding System Organ Class (SOC), and reported based on the MedDRA preferred term (PT) applicable. In addition, patients in both treatment groups were contacted by telephone by the research team to evaluate the adverse event presence.

The present study was developed, until its conclusion, following the legal provisions of the General Health Law of the United Mexican States, the Official Mexican Law NOM-012-SSA3-current version, to the Official Mexican Law NOM-220-SSA1-current version, and in accordance with the Helsinki Declaration of 1964 and its later amendments.

The study protocol, informed consent form (ICF), and any other relevant documents according to National Regulation were reviewed and approved by an independent ethics committee (IECs) (Research Committee of Investigación Biomédica para el Desarrollo de Fármacos, S.A. de C.V.) with the approval Number: CEI-000002, and the Health Authority (Federal Commission for the Protection against Sanitary Risks [COFEPRIS]) with the approval Number: 213300410A0125/2021. All patients included in this study provided written informed consent.

Data analysis were conducted for the intent-to-treat population defined as all patients who were randomized and received at least one dose of the study drug. To assess the homogeneity of the treatment groups, the baseline characteristics were analyzed using the Mann–Whitney U test (continuous variables), while the categorical variables were analyzed using the chi-square test. Changes from baseline in VAS scores to each post-baseline evaluation were analyzed using a repeated measures analysis of variance (ANOVA) from obtaining the deltas (∆) of change in pain assessments on days 3, 5, and 7 concerning their baseline measurement, adjusted for sex as a covariant. To test differences over time (within groups), McNemar test was applied for categorical variables and Wilcoxon signed-rank test was used for continuous variables, and to test differences over time (between group), Mann–Whitney U test was applied. Values of p < 0.05 were considered statistically significant. All tests were performed with IBM SPSS Statistics for Windows, version 28 (IBM Corp. Armonk, NY, USA).

Results

This study included 139 patients who underwent screening between September and December 2021, of which 124 patients were randomized to receive either etoricoxib/tramadol (n = 61) or paracetamol/tramadol (n = 63) (Fig. 1). During follow-up, two patients dropped out (both in paracetamol/tramadol group). Table 1 shows the basal parameters and clinical characteristics; median age in both groups was similar (48 years, etoricoxib/tramadol; 46 years, paracetamol/tramadol). The comorbidities detected were diabetes (group A, 1.6%; group B, 7.9%), hypertension (group A, 8.2%; group B, 4.8%), and allergies (group A, 6.6%; group B, 11.1%). There were no clinically significant differences between groups. Most acute low back pain episodes reported in both treatment groups were mechanical (93.4% for etoricoxib/tramadol and 96.8% for paracetamol/tramadol; p = 0.436) and occurred within a short period. Non-specific causes were reported in 6.6% of etoricoxib/tramadol patients and 3.2% of comparator treatments.

Fig. 1
figure 1

Patient disposition. ITT intention-to-treat, ICF informed consent form, mg milligrams

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Table 1 Baseline sociodemographic, anthropometric, clinical and biochemical characteristics of patients admitted to the study by treatment groups
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For the primary efficacy outcome, changes in pain intensity were comparable for both treatments (Table 2). With a baseline VAS expressed as a mean (SEM), of 7.1 (0.1) and 6.8 (0.1), for etoricoxib/tramadol and paracetamol/tramadol group, respectively (p = 0.272).

Table 2 Changes in primary efficacy parameter (pain intensity on the VAS) during the follow-up between etoricoxib/tramadol and paracetamol/tramadol
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For the comparison of magnitude of change in pain intensity over time (∆), an ANOVA model of repeated measures was carried out and adjusted for sex as a covariate. All estimated means were adjusted for several comparisons by Bonferroni, and all effects were reported as significant p < 0.05.

From obtaining the magnitude of change (delta [∆] and %) of pain evaluations on days 3, 5, and 7 concerning baseline, we identified a superior magnitude of change on each day evaluation from etoricoxib/tramadol compared to paracetamol/tramadol group.

The VAS values changes, Δ (% of change) at days 3, 5, and 7 for etoricoxib/tramadol group were − 2.8 (− 38.3), − 4.6 (− 63.9) and − 5.3 (− 72.7), respectively. For paracetamol/tramadol group the Δ values were − 2.1 (− 29.6), − 3.8 (− 54.5) and − 4.8 (− 68.6), for each of the follow-up visits. These results indicate a greater reduction in pain intensity for the patients in etoricoxib/tramadol group compared with paracetamol/tramadol (Fig. 2).

Fig. 2
figure 2

Magnitude of change in pain intensity at day 3, 5, and 7 with respect to its baseline measurement by treatment group. Notes: Phone call 1 (follow-up) = evaluation day 3, phone call 2 (follow-up) = evaluation day 5, visit 2 = evaluation day 7. Repeated measures ANOVA, adjusted for sex as a covariate. All estimated means were adjusted for various comparisons by Bonferroni, and all effects were reported as significant p < 0.05. QD one a day, TID three times a day, VAS Visual Analog Scale, ∆ delta

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Specifically, VAS values changes at day 5 in etoricoxib/tramadol group − 4.6 (− 63.9) were better compared with the obtained in paracetamol/tramadol group − 3.8 (− 54.5). These improvements represent a statistically significant difference (p = 0.041).

In addition, within the treatment groups, differences were found in the multiple comparisons of the days in which the change in pain intensity was evaluated (p = 0.001).

Moreover, an analysis was carried out to determine the proportion of patients who responded to treatment. On the third day of follow-up, the proportion of patients who rated pain intensity with a ≥ 30% reduction (VAS) was superior in etoricoxib/tramadol compared to paracetamol/tramadol group: 59.0 vs. 34.9%, [p = 0.008] (Fig. 3). The proportion of patients with this score increased on fifth day (82%, group A; 76.2% group B) and seventh day of follow-up (86.9%, group A; 78.7%, group B, Table 3), which demonstrates a greater reduction in the group under treatment with etoricoxib/tramadol. The clinical response to the intervention was also assessed by looking at the number of patients who experienced a 50% reduction in pain intensity during the follow-up period. Statistically significant differences were found when comparing the treatment groups, especially on the third day (37.7 vs. 19%, [p = 0.026]). The group treated with etoricoxib/tramadol maintained a higher response rate (Table 4).

Fig. 3
figure 3

Percentage of patients who responded to the intervention (30% reduction in Visual Analogue Scale [VAS]) during the follow-up by treatment group

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Table 3 Proportion of patients responded to treatment with a ≥ 30% reduction in intensity pain VAS by the treatment group
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Table 4 Proportion of patients responded to treatment with a ≥ 50% reduction in intensity pain VAS by the treatment group
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As well to VAS, the improvement in the disability to perform daily life activities due to acute low back pain was evaluated between treatment groups. Between baseline and final measurements in both treatment groups, statistically significant differences were observed (p = 0.001) both in ODI and RMDQ questionnaires. Between treatment groups, an improvement in the bothersomeness to perform daily activities, determined by RMDQ, with etoricoxib/tramadol was observed (p = 0.068). Besides, differences were found in the percentage of disability due to lumbar pain, determined by ODI, between baseline and final measurement in both treatment groups (p = 0.001) but not so between treatment groups (p = 0.453) (Table 5).

Table 5 Changes in secondary efficacy parameters during the follow-up between etoricoxib/tramadol and paracetamol/tramadol
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For the safety analysis, the information of 124 patients was evaluated, of which, 38 subjects reported at least one adverse event (AE). Among these, 16 patients (26.2%) were in etoricoxib/tramadol group, and 22 (34.9%) were in paracetamol/tramadol group. A total of 79 AEs were reported, with 48.1% (38 events) associated with etoricoxib/tramadol and 51.9% (41 events) associated with the comparator. In the study, five patients discontinued treatment due to adverse events. In the etoricoxib/tramadol group, one patient stopped treatment due to side effects (erythema, gastritis, insomnia, and dysgeusia). In the paracetamol/tramadol group, four patients discontinued therapy due to side effects (nausea, vomiting, pruritus, somnolence, and diaphoresis). All of them were classified as non-serious (100%). No deaths were reported in the study. According to the severity of the event, a higher proportion of AEs were classified as “mild” compared to "moderate" was observed in both treatments (73.4 vs. 26.6%). The severity of the adverse events was greater in paracetamol/tramadol group compared to etoricoxib/tramadol (41.5 vs. 10.5%), this difference was considered statistically significant (p = 0.002).

The most affected SOCs were gastrointestinal disorders and nervous system disorders, with 33 (41.7%) events (19 [57.5%] in etoricoxib/tramadol group and 14 [42.5%] in paracetamol/tramadol group) and 32 (40.5%) events (14 [43.7%] in the etoricoxib/tramadol group and 18 [56.3%] in the paracetamol/tramadol group), respectively. The most frequent events were nausea (17.7%) and dizziness (16.4%) (Table 6).

Table 6 Adverse events reported during the follow-up in etoricoxib/tramadol and paracetamol/tramadol group
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Finally, regarding the rescue medication, the proportion of patients who required it was higher in paracetamol/tramadol group compared to etoricoxib/tramadol group (11.1 vs. 6.6%, [p = 0.530], respectively).

No clinically significant differences were observed in vital signs and biochemical / hematological laboratory parameters.

Discussion

Pain management demands the generation of strategies for earlier, more effective, and safer relief that limits its progression to chronic pain. The management of acute low back pain should focus on immediate emergencies that prevent the development of future complications associated with disability, important to flourishing the patient's quality of life.

Given the complex pathophysiology of pain, multimodal analgesia has been implemented as a therapeutic strategy, defined as the simultaneous use of drugs with different complementary mechanisms of action that generate a synergistic or additive effect. Several drugs are commonly used in multimodal analgesia including opioids, NSAIDs, and paracetamol [25,26,27].

Within the available scientific literature, a study evaluated the possible interactions (additive, potentiation, or synergy) in the antinociceptive effects of etoricoxib and tramadol in combination against mechanical hyperalgesia induced by spinal cord injury in rats. They concluded that the synergistic antihyperalgesic action of this combination has clinical utility in mechanical hyperalgesia associated with spinal injury [28].

Different FDCs have been evaluated in the treatment of pain, including paracetamol/tramadol, diclofenac/tramadol, codeine/ibuprofen, codeine/paracetamol, oxycodone/paracetamol, and dexketoprofen/tramadol, either compared to the drug alone or versus any of these combinations. Like etoricoxib/tramadol, other combinations of NSAIDs with tramadol have been evaluated against paracetamol/tramadol, showing similar results in terms of pain management. In 2006, Chandenwale et al. evaluated the analgesic efficacy of diclofenac/tramadol FDC versus paracetamol/tramadol in patients with acute musculoskeletal conditions, postoperative pain after orthopedic surgery, osteoarthritis, and rheumatoid arthritis, identifying a greater reduction in pain intensity and lower frequency of adverse events with the diclofenac/tramadol combination after 5 days of treatment. This study presented superior results observed with the FDC of diclofenac/tramadol through a scheme with a lower dosage (one tablet twice a day vs. two tablets every 4–6 h without exceeding eight tablets), greater adherence, and fewer reports of adverse events [14].

Currently, the recommended treatment for low back pain is a combination of paracetamol 325 mg and tramadol 37.5 mg, based on a minimum dosage schedule of three doses and a maximum of ten doses in 24 h, the equivalent of 975 mg to 3250 mg of paracetamol and 112.5 mg to 375 mg of tramadol per day, for a period of up to 4 weeks, this treatment represents one of the most widely prescribed, although it is not necessarily the safest analgesic regimen [15, 25]. A single-dose schedule combining a COX-2 selective NSAID with a weak opioid (etoricoxib 90 mg/tramadol 50 mg) has shown better results compared to the standard therapy. This combination demonstrates that the anti-inflammatory effects of etoricoxib and tramadol together have a stronger analgesic effect with a lower dose, as compared to the paracetamol/tramadol combination.

The combination of etoricoxib/tramadol provides effective pain relief through multimodal management due to the different mechanisms of action of its components, achieving a faster reduction in pain intensity compared to conventional therapy. The multimodal approach provided by this combination not only improves treatment adherence but also achieves an opioid-sparing effect (pain control with lower doses of opioids and thus lower incidence of opioid-related adverse events) [13]. For low back pain, it is suggested that multimodal analgesic regimens be preferred over monotherapy and, even more so, over opioid management, through timely interventions, to provide immediate pain relief and prevent pain develop chronic low back [25]. Regarding the safety of the investigation products, there were no significant new data found that have not been previously reported for products used in monotherapy regimens.

The opioid-sparing effect associated with NSAIDs has been previously studied. Langford et al., conducted a study to evaluate the efficacy and safety of a tramadol/celecoxib co-crystal in patients with acute moderate to severe pain after abdominal hysterectomy. Patients were randomized into the following treatment groups: tramadol/celecoxib twice daily (BID) (doses of 44 mg/56 mg, 66 mg/84 mg, or 88 mg/112 mg), tramadol 100 mg four times daily, celecoxib 100 mg BID, all treatments were carried out for 5 days. Demonstrating that all doses of tramadol/celecoxib were equally effective as tramadol alone for the treatment of pain. Additionally, it was observed that despite the dosing schedule, a lower cumulative delivery of tramadol was obtained in the tramadol/celecoxib 88 mg/112 mg, BID group (cumulative dose of 880 mg) compared to tramadol 100 mg once daily (cumulative dose of 2000 mg). Serious and non-serious adverse events were less common in the tramadol/celecoxib group compared to the tramadol alone group [29].

López-Cedrún et al., conducted a study to evaluate the efficacy and safety of a tramadol/celecoxib co-crystal in patients with acute moderate to severe pain after oral surgery. Patients were randomized into the following single-dose treatment groups: tramadol/celecoxib (doses of 44 mg/56 mg, 66 mg/84 mg, or 88 mg/112 mg), tramadol 100 mg or placebo, demonstrating that all doses of tramadol/celecoxib were equally effective as tramadol alone for the treatment of pain. The opioid-sparing effect was 56% and 34% in the tramadol/celecoxib group at doses of 66 mg/84 mg and 88 mg/112 mg, respectively. The proportion of serious and non-serious adverse events was lower in the tramadol/celecoxib group compared to the tramadol alone group. This approach improved tolerability while improving efficacy [27].

In this clinical study, the cumulative doses of opioids throughout treatment were 787.5 mg, and 350 mg in FDC paracetamol/tramadol and FDC etoricoxib/tramadol group, respectively, which represent a 55.9% reduction in the daily dose of tramadol used. The opioid-sparing effect obtained in the present study is consistent with those reported in the scientific literature.

The results published by Langford et al. [29] and López-Cedrún et al. [27] are similar to those obtained in this study. Where the combination of tramadol with a NSAIDs not only reduces the dose of opioid used (with subsequent improvement in the safety profile) but at the same time maintains the expected therapeutic efficacy.

The definition of a clinically significant change in pain intensity is undoubtedly highly variable from study to study. In this study, the investigational drug (FDC etoricoxib 90 mg/tramadol 50 mg) is indicated in a single-dose posology QD and exhibited superior therapeutic effects on day 5 (p = 0.041) and a greater proportion of patients who responded to treatment throughout the follow-up compared to FDC paracetamol 325 mg mg/tramadol 37.5 mg (administered TID for a final daily dose of 975 mg/112.5 mg, respectively).

Moreover, the data obtained shows that FDC therapy with etoricoxib 90 mg/tramadol 50 mg once daily exhibits analgesic synergy and greater pharmacological potency compared with standard therapy (same therapeutic effect obtained with a lower dose of each drug).

It was possible to identify that a higher proportion of patients in the etoricoxib/tramadol group reported a reduction in pain intensity ≥ 30% in an earlier period (the first 3 days) compared to the paracetamol/tramadol group. These data coincide with those reported by Meloncelli et al. in a study that compared the analgesic efficacy and tolerability of the tramadol/dexketoprofen 75 mg/25 mg combination versus diclofenac 75 mg/thiocolchicoside 4 mg in patients with acute low back pain, they observed that the highest proportion of subjects who responded (defined as a reduction pain intensity of at least 30%) to treatment corresponded to the group with the combination of tramadol/dexketoprofen [30].

In the clinical study reported by Langford et al. [29] the 50% response rate (reduction in pain intensity ≥ 50%) at 4 h was evaluated, with a 23.2% for tramadol/celecoxib (44 mg/56 mg), 24.6% for tramadol/celecoxib (66 mg/84 mg), 30.8% for tramadol/celecoxib (88 mg/112 mg), 30.8% for tramadol and 23.8% for celecoxib. The results showed that there was no significant difference between the treatment groups for the speed of pain reduction. Additionally, all doses of tramadol/celecoxib were equally effective as tramadol alone for the management of pain at the end of treatment. These results are different to those obtained in this clinical study, in which a superior clinical improvement with etoricoxib/tramadol was achieved (p = 0.008) in an acute period (3 days).

The results listed above show the clinical benefits of the etoricoxib/tramadol in a convenient dosage form (granules), such as faster therapeutic response, therapeutic equivalence at the end of the evaluation period, and opioid-sparing effect (reduction of 55.9% of the dose of tramadol per day), which translates into; decrease in the risk of dependence, the incidence of adverse events dependent on the dose of tramadol (such as nausea, vomiting, drowsiness, etc.), reduction in pill load, and subsequent better therapeutic adherence [13].

Additionally, better therapeutic adherence was observed in the etoricoxib 90 mg/tramadol 50 mg group compared to paracetamol 975 mg/tramadol 112.5 mg, a result related to the dosage scheme; once daily versus three times a day, respectively. However, this improved therapeutic adherence is also a result of accelerated pain reduction in the etoricoxib 90 mg/tramadol 50 mg group, as it has been shown that treatment adherence in pathologies that cause pain are conditioned by the therapeutic effect obtained in the first days of treatment [31].

Another aspect of great importance was the proportion of subjects who required the use of the rescue drug, being higher in paracetamol/tramadol group (6.6 vs. 11.1%). These results are similar to those reported by Chandanwale, whose study identified a higher proportion of subjects who required rescue medication in paracetamol/tramadol group (8.9 vs. 21.7%) [14], and similar to those reported by Langford et al. [29] with a 20.9% of patients used rescue medication in the first 4 h in tramadol/celecoxib (44 mg/56 mg) group, 16% for tramadol/celecoxib (66 mg/84 mg), 17.0% for tramadol/celecoxib (88 mg/112 mg) and 18.4% for the tramadol group.

As a response to adequate pain management, the next objective is the functional recovery of the patient, promoting his reintegration into the activities he usually performed [25]. As part of this study in terms of disability improvement, no statistically significant differences were observed between the treatment groups (etoricoxib/tramadol vs. paracetamol/tramadol), however, statistically significant differences (p = 0.001) were observed in both groups between the degree of low back pain and the inability to perform daily activities at the beginning and end of the intervention: Oswestry Disability Index scores, baseline, and follow-up for etoricoxib/tramadol and paracetamol/tramadol; 28 to 6 and 32 to 8, respectively. Roland–Morris Disability scores; baseline, and follow-up for etoricoxib/tramadol and paracetamol/tramadol; 8 to 1 and 8 to 2, respectively. Corroborating the therapeutic efficacy of both investigational products.

Regarding the safety profile of both treatments, no relevant data was found that had not been previously reported on the products used as monotherapy. Among all adverse events reported in our study, the etoricoxib/tramadol group reported a lower proportion of AEs compared to the group receiving paracetamol/tramadol.

The main adverse events reported were nausea, dizziness, and drowsiness, these occurred in a lower proportion in the etoricoxib/tramadol group. In both groups, gastrointestinal disturbances and side effects related to the use of NSAIDs were reported, although to a lesser extent than those reported in studies that integrate non-selective COX2 inhibitors. It should be noted that, depending on the severity of the event, a higher proportion of AEs classified as “mild” versus “moderate” was observed in both treatments, where the paracetamol/tramadol group reported more severe adverse events, compared to etoricoxib/tramadol.

The efficacy of the FDC under study occurred while maintaining a similar or improved safety profile compared to that of paracetamol/tramadol, this result was achieved thanks to the administration of lower concentrations of each active drug, mainly tramadol. No warning signs or risks were identified that could modify the benefit–risk balance of the patients with the use of the study drugs, so the safety profile remains favorable.

Finally, the pharmacokinetic profile of the etoricoxib/tramadol FDC formula and concomitant dosing was evaluated in the study BD ET-Sil No. 112–19, observing that there are no statistically significant differences, in the values of maximum plasma drug concentration (Cmax), the area under the plasma drug concentration–time curve from 0 up to the last sampling time (AUC0–t), and the area under the plasma drug concentration–time curve from 0 up to infinity (AUC0–inf) for etoricoxib; confidence intervals (CI) 90% 95.92–114.26, 96.84–105.20, and 95.99–105.10, respectively, and tramadol CI90%; 99.42–116.16, 110.65–122.91, and 110.25–121.87, respectively. These results demonstrate that the reduction in tramadol dosage (opioid-sparing effect) is not related to pharmacokinetic differences of the etoricoxib/tramadol FDC, but a pharmacodynamic synergic effect of the drugs [32].

Although in the present study the efficacy and safety of etoricoxib/tramadol FDC was demonstrated, it would be interesting to explore the minimum therapeutic response time; performed with more constant pain measurements at shorter time intervals (e.g., VAS at 6, 12, 24, and 48 h). This analysis could provide valuable information on the clinical benefits of the investigational product. Another limitation of the study could be the small sample size due to which the results could not be completely extrapolated to the general population.

Conclusions

The data collected from patients in this study validates the efficacy and safety of both treatments for managing acute low back pain over 7 days. The results show a consistent reduction in pain intensity and improvement in the ability to perform daily activities. These findings highlight the clinical benefits of the etoricoxib/tramadol combination, including rapid therapeutic response, greater reduction in pain by the third and fifth day of treatment, and comparable efficacy to paracetamol/tramadol by the seventh day. This clinical trial indicates that it is possible to improve the safety profile while maintaining or enhancing efficacy using lower analgesic doses (etoricoxib and tramadol) through a fixed-dose combination approach.