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.