FormalPara Key Points

The fixed-dose combination (FDC) of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins led to a substantial reduction in pain intensity since the third day of treatment, maintaining this difference until the end of the 7-day intervention period.

The FDC not only diminishes the risk of adverse reactions to nonsteroidal anti-inflammtory drugs but also facilitates a quicker return to daily activities for patients.

1 Introduction

Musculoskeletal system pathologies are recognized as a common cause of work absenteeism. Among them, neck and spine disorders stand out as important contributors to morbidity. In the last decade, the global incidence of neck pain cases was 47.5 million and 22.1 million years of healthy life lost (YLDs) [1]. Musculoskeletal disorders ranked as the third leading cause of YLDs in Mexico, contributing to 1.95 million disability-adjusted life-years (DALYs). In Mexico, 17.5 million individuals experience limitations due to stiffness, fatigue, and pain associated with these type of disorders. These conditions significantly affect various aspects of daily life, including restricted mobility, hindered work capacity, diminished independence, and a decline in mental health [2].

It is well known that neck pain has multiple etiologies, including physical and psychosomatic factors. According to the Cervical Sprain Clinical Practice Guidelines, these can be divided into two categories, i.e. post-traumatic and degenerative, with the first category covering flexion, extension and lateralization mechanisms. Degenerative conditions include degenerative spondylitis, among others, considering that some degenerative cases may be secondary to previous injuries. In traumatic etiologies, the terms cervical sprain, acceleration neck injury, and whiplash injury are often use interchangeably to describe an injury characterized by a rapid neck hyperextension followed by a hyperflexion. Clinical practice guidelines define cervical sprain as an injury that combines extension and flexion of the tissues of the cervical spine, caused by the acceleration and deceleration of energy transmitted to the neck [3, 4].

Traffic accidents are the most common cause of neck pain, although it may also be related to other factors such as falls, violent assaults and sports injuries, especially in contact sports. Approximately 20% of people involved in car accidents experience symptoms in the cervical region, and about 25% develop chronic pain in that area. Alteration of the cervical region caused during an accident induces the expansion of muscle fibres, ligaments and nerve structures in the cervical region, contributing significantly to the development of soft tissue injuries. These lesions are attributed to inflammatory processes, which manifest as neck pain and are associated with stiffness resulting from contraction of the neck muscles [5, 6].

In 1995, the Quebec Task Force, an international group dedicated to studying whiplash-associated disorders (WAD), conducted a comprehensive review of scientific evidence to establish guidelines for the diagnosis, treatment, and prognosis of WAD [7]. During this review, the Quebec Task Force categorized whiplash injuries into three levels of cervical sprains, i.e. I, II, and III, with each corresponding to a distinct set of symptoms. Furthermore, the Quebec classification for cervical sprains and related disorders introduced a fourth degree to encompass cervical trauma cases that involve both neck complaints and the presence of cervical spine fractures or instability [8, 9].

There is no specific treatment for neck pain, since an abundance of therapeutic options have been proposed to treat this pathology, as it is not thoroughly understood. In general, two main types of treatments are commonly used. The typical initial approach involves pharmacological treatment with anti-inflammatories and/or muscle relaxants, along with immobilization of the cervical spine using a cervical collar (soft or hard) and rest. In several guidelines for the management of whiplash-associated disorders, it has been reported that nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line recommended pharmacological treatment; however, their use should be restricted, taking into consideration the potential adverse effects associated with dose response [4].

Dexketoprofen has been formulated as a tromethamine salt; this corresponds to a water-soluble salt of the dextro-rotating enantiomer of ketoprofen, which is a racemic mixture NSAID that has been described as an inhibitor of both cyclooxygenase (COX)-1 and COX-2. The analgesic effect of dexketoprofen initiates approximately 30 min following oral intake and has a duration of about 4–6 h, which is not affected by factors such as sex or age [10].

The thiamine + pyridoxine + cyanocobalamin vitamins are a group of water-soluble compounds that play a crucial role in the proper functioning of the peripheral nervous system [11]. Their effectiveness is enhanced when administered in combination orally, especially vitamins such as thiamine, pyridoxine and cyanocobalamin, which have been used not only in the treatment of pain and inflammation resulting from vitamin deficiency but also in combination with specific NSAIDs for assorted painful diseases such as neuropathies with various causes, degenerative diseases of the spine, rheumatic diseases, and lumbago, among others [12]. Several mechanisms of action for these vitamins have been studied over the years, among which are the increase in the production of different neurotransmitters that participate in the modulatory pathway of pain, the regulation of the inflammatory and antioxidant response, and the activation of adenosine receptors in nociceptive neurons of the ganglion of the dorsal root [13,14,15].

The clinical use of analgesic combinations has increased significantly in recent years. The objective is to associate two or more compounds with different mechanisms of action, with the purpose of achieving a synergistic interaction that results in effective pain relief using lower doses of each drug. This approach aims to minimize the severity and occurrence of adverse effects [16]. Because of the information surrounding analgesic combinations, and more specifically the use of vitamin B with NSAIDs as pain treatment, the objective of this study was to demonstrate the analgesic synergy of a fixed-dose combination (FDC) of dexketoprofen and the combination of thiamine + pyridoxine + cyanocobalamin vitamins in the treatment of acute pain caused by grade I–II cervical sprains.

2 Patients and Methods

A phase IIIb, prospective, randomized, double-blind, multicentre study was conducted to evaluate the efficacy and safety of the FDC of dexketoprofen and vitamin B (thiamine, pyridoxine and cyanocobalamin) compared with dexketoprofen monotherapy in the management of acute pain in patients with grade I–II cervical sprains according to the Quebec scale. This trial is considered a non-inferiority study, since the research intends to compare a novel intervention (dexketoprofen/vitamin B [thiamine + pyridoxine + cyanocobalamin] in the FDC) versus standard treatment (dexketoprofen).

Subjects of both sexes, who voluntarily agreed to participate by giving their written informed consent, were enrolled. Participants were required to be at least 18 years of age at the beginning of the study. The study included participants diagnosed with grade I or II cervical sprain on the Quebec scale, with ≤ 3 days of evolution, and whose evaluation of the visual analogue scale (VAS) was ≥ 4 cm. Women of childbearing age currently using an approved contraceptive method, such as barrier, hormonal, injectable, subdermal, menopausal or surgically sterile, were also included. Exclusion criteria included previous treatment with opioids reported in the medical history; history of inflammatory arthritis (e.g., rheumatoid arthritis, ankylosing spondylitis, gout), chronic pain (e.g., fibromyalgia), metastasis and Paget’s disease; clinical and radiological grade III or IV cervical sprain data; symptoms of spinal cord injury; history of severe acute or chronic liver failure, moderate to severe renal failure and coagulation problems (Fig. 1).

Fig. 1
figure 1

Flowchart of study enrollment and allocation

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The selection process involved gathering a comprehensive medical history and conducting clinical laboratory tests. All patients had an x-ray of the cervical spine (anteroposterior and lateral) performed within a period of no more than 72 h, with the intention of ruling out an injury of greater severity than established. After the selected patients had signed their informed consent form, they were randomized to either the dexketoprofen 25 mg/vitamin B capsule (thiamine 100 mg, pyridoxine 50 mg, cyanocobalamin 0.50 mg) or dexketoprofen 25 mg tablet (orally, every 8 h, for 7 days) treatment groups. Patients were followed-up for 7 days, which included three in-person visits (on days 0, 3 and 7) and two phone calls (on days 1 and 5). Simple randomization was performed through the www.randomizer.org platform, balanced by treatment. Sealed randomization envelopes for each of the kits were used. The patient and investigator were blinded for the assignment of the treatments. The blinding methods were homologation of the secondary packaging; the sponsor was in charge of providing the randomized medications, while the distribution of the study treatments at each visit was carried out by the personnel delegated by the principal investigator.

2.1 Outcomes Measures

The primary efficacy outcome was defined as the mean change in pain intensity assessed using a VAS, which consisted of a 10 cm straight line with one end indicating the absence of pain and the opposite end representing the worst severe pain imaginable. During each in-person visit (days 0, 3 and 7), patients were instructed to place a mark on the scale indicating the current pain level. Follow-up phone calls were made (at days 1 and 5), during which the physician questioned and documented the reported value.

Additionally, as a secondary outcome, the Spanish validated version of the Northwick Park Neck Pain Questionnaire (NPQ) [17] was applied to the study participants to assess how cervical pain could influence their daily life. The questionnaire consisted of nine items covering various aspects, including the intensity of cervical pain, its effect on sleep quality and quantity, nocturnal arm pricks or tingling, symptom duration, and impact on activities such as lifting, reading, watching television, work, social interactions, and driving. Each of these items had five possible responses, ranging from zero to four, signifying increasing intensity and severity, respectively. This evaluation was conducted on five occasions, three during face-to-face visits (days 0, 3 and 7) and two through phone calls (days 1 and 5).

Regarding safety outcomes, patients were instructed to maintain a diary in which they documented and reported any signs or symptoms experienced throughout their participation in the study (7 days follow-up). Furthermore, the investigators conducted assessments intentionally directed at identifying possible adverse events.

This study was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. The Institutional Ethics Committee and the Research Committee of Investigación Biomédica para el Desarrollo de Fármacos S.A. de C.V. approved the clinical study (protocol approval number: CEI-000001). Additionally, approval from the Ministry of Health in Mexico (COFEPRIS; approval no. 213300410A0152/2021) was obtained before study execution. All patients provided written informed consent to participate. The study protocol was registered and uploaded at ClinicalTrials.gov (identifier: NCT05001555).

2.2 Statistical Analysis

Baseline characteristics such as sociodemographic, anthropometric, clinical and biochemical variables were described by treatment group, with this information presented according to their corresponding measures of central tendency and dispersion. For quantitative variables, the Kolmogorov–Smirnov test was used to identify whether these variables adjusted to the assumptions of normality. The results were reported in tables and graphs as means and standard deviations or median and interquartile range, while the categorical data were presented as frequencies and percentages.

The sample size was calculated with a confidence level of 95% (α = 0.05) and a statistical power of 90%, considering a minimum detectable difference in pain relief of 25% between the treatment groups and anticipating a 20% dropout rate, obtaining a total sample size of 172 patients [18].

The final mean, average change and percentage of change in pain perception (measured through the VAS) were compared with the baseline measurement through the paired T-test or its non-parametric Wilcoxon rank-sum test, depending on the distribution of the data. These results were compared between the treatment groups using the independent t-test or its non-parametric Mann–Whitney test. To evaluate the effect of both treatments on pain management throughout the course of the study, repeated measures analysis of variance (ANOVA) was performed, with post hoc comparisons adjusted by Bonferroni correction. Incidence rates for adverse events were summarized by the number of subjects with at least one event per system organ class (SOC)/preferred term in the current Medical Dictionary for Regulatory Activities (MedDRA) version 26.1.

Similar tables were presented involving severity and intensity and according to the causality or imputability to any of the treatments under investigation. A p value < 0.05 was considered significant. All analyses were conducted using SPSS software, v.29.0 for Windows (IBM Corporation, Armonk, NY, USA).

3 Results

A total of 170 patients were included and randomized to one of the two treatment groups under study—83 subjects in the dexketoprofen/vitamin B group and 87 in the dexketoprofen group. All patients were followed-up for 7 days. In the comparison between groups for baseline characteristics, no statistically significant differences were observed, thus demonstrating that the groups began under homogeneous conditions. Likewise, no differences were observed for the characteristics of the injury (Table 1).

Table 1 Baseline demographic, anthropometric, biochemical and clinical characteristics of the subjects included in the study, by treatment group
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An analysis was carried out for the main variable of pain intensity, with the reported VAS scores at 24 h and 3, 5 and 7 days of intervention, which were compared with the baseline evaluation. Table 2 shows the results for the mean pain intensity during each of the follow-ups, as well as the p value obtained from the comparison against the baseline evaluation. Statistically significant differences were observed from the third day of treatment (p = 0.003), showing the greatest difference between the groups on day 5 of the intervention, with a mean of 2.4 ± 1.4 cm for the dexketoprofen/vitamin B group and 3.3 ± 1.8 cm for dexketoprofen group (p = 0.001), and maintaining this difference until the end of the 7-day treatment (p = 0.017). Similarly, Table 3 shows the percentage change for each of the follow-ups, observing statistical differences between the treatments on days 3 and 5 (p = 0.016 and 0.004, respectively) and total percentage change of up to − 79.6% for the dexketoprofen/vitamin B group and − 74.5% for the dexketoprofen group at the end of the clinical study.

Table 2 Pain intensity evaluated by visual analogue scale at 24 h and 3, 5 and 7 days compared with baseline
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Table 3 Percentage change in visual analogue scale scores at 24 h and 3, 5 and 7 days, by treatment group
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Likewise, the mean changes for each of the follow-ups were compared in order to observe the decrease in pain intensity at each of the evaluated times. Differences were observed on days 3 and 5 of the intervention (p = 0.011 and p = 0.003, respectively), with mean changes of − 3.1 ± − 1.5 cm for deketoprofen/vitamin B versus − 2.6 ± − 1.1 cm for the dexketoprofen group on the third day, − 4.7 ± − 1.7 cm versus − 3.9 ± − 1.6 cm for the 5th day, and a final reduction of − 5.7 ± − 1.7 cm (dexketoprofen/vitamin B) and − 5.4 ± − 1.6 cm (dexketoprofen) by the end of the study. Figure 2 shows the changes over time for each treatment.

Fig. 2
figure 2

Mean change in pain intensity measured by visual analogue scale throughout the 7 days of intervention, by treatment group. Difference between groups was obtained using the independent t test. VAS visual analogue scale

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Regarding the degree of disability due to neck pain, patients were evaluated in the same way, at 24 h and 3, 5 and 7 days, and the percentages obtained were compared with their baseline evaluation. Significant differences within the same group were observed in the comparisons for all follow-ups, showing important changes in the percentage of disability from day 1 of treatment. For the comparison between the dexketoprofen/vitamin B and dexketoprofen treatment groups, a statistically significant difference was observed for the final measurement at 7 days of intervention (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028 (Table 4).

Table 4 Change in the percentage of disability degree according to the Northwick Park Neck Pain Questionnaire at 24 h and 3, 5 and 7 days compared with baseline
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An analysis of the mean changes obtained for the NPQ throughout the follow-ups was performed. Figure 3 shows the reduction in the percentage of disability degree in both groups. It was observed that the dexketoprofen/vitamin B treatment had a greater decrease throughout the 7 days of follow-up compared with dexketoprofen treatment. It was during day 3 of the study that a statistically significant difference was found between the treatments groups (p = 0.045).

Fig. 3
figure 3

Mean change in the percentage of disability degree according to the Northwick Park Neck Pain Questionnaire (NPQ) at 24 h, 3, 5 and 7 days

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During the clinical trial, 45 adverse events were recorded in 36 patients (16 in the dexketoprofen/vitamin B group and 29 in the dexketoprofen group). There were no serious events reported; 68.9% were of possible causality, and 65.5% of these occurred in the dexketoprofen group. In relation to severity, the dexketoprofen group had a higher percentage of moderate adverse events compared with the dexketoprofen/vitamin B group (6.2% vs. 41.4%). The most prevalent adverse events were gastritis (26.6%), nausea (11.1%) and drowsiness (13.3%); gastrointestinal disorders were the most common in the dexketoprofen group compared with the dexketoprofen/vitamin B group (64.3 and 35.7%, respectively). The complete description of adverse events is reported in Table 5.

Table 5 Description of adverse events presented throughout the study, by treatment group
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4 Discussion

The results obtained from this randomized controlled trial involving 170 patients with neck pain demonstrated a significant difference in pain intensity and disability between the group treated with the FDC of dexketoprofen/vitamin B and the group treated with dexketoprofen monotherapy. The study findings revealed that the FDC led to a substantial reduction in pain intensity, as measured by VAS scores, starting from the third day of treatment and maintaining this difference until the end of the 7-day intervention period. Moreover, the analysis of disability due to neck pain assessed through the percentage of disability by the NQP showed significant improvements in both groups over the follow-up period. However, the FDC of dexketoprofen/vitamin B exhibited a statistically significant advantage over the monotherapy group at the final measurement after 7 days of intervention.

Regarding the mechanisms of action by which B vitamins (thiamine, pyridoxine and cyanocobalamin) produce their therapeutic effects, it should be mentioned that there is no single pharmacodynamic route and that there is evidence involving different pathways for pain in which these agents can produce analgesia. For instance, modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems; pyridoxine alone or in combination with thiamine and cyanocobalamin is able to increase the synthesis and secretion of serotonin in several brain regions, thus regulating pain intensity [19, 20]. Furthermore, an additional mechanism of action for the analgesic effect of B vitamins has been associated with the spinothalamic tract, which represents the most important ascending pathway for pain. Experimental animal models have shown B vitamins to be associated with an increase in inhibitory control of afferent nociceptive neurons in the spinal cord and a reduced response of thalamic neurons to nociceptive stimulation [21, 22].

Recent studies have shown that B vitamins play a synergistic role in the analgesic effect of agents such as opioids through novel mechanisms. After the administration of intracerebroventricular B vitamins in rats under formalin-induced muscle pain, a potential effect on opioid receptors was demonstrated. The antinociceptive effects of B vitamins occurred in the absence of naloxone; however, it was evident that when naloxone was administered, the analgesic effect of these compounds was diminished. It was confirmed that the analgesic effects induced were partially blocked by naloxone, suggesting that these vitamins could release endogenous opioids that could activate opioid receptors [23].

Several clinical studies, a systematic review, and a meta-analysis collectively highlighted the safety and benefits associated with combining NSAIDs and B vitamins compared with using NSAIDs alone in the management of acute neuropathic back pain (NBS) and exacerbations of chronic NBS. The incorporation of B vitamins alongside NSAIDs has shown to reduce the treatment duration in half. This reduction in pharmacotherapy duration not only diminishes the risk of adverse reactions to NSAIDs but also facilitates a quicker return to daily activities for the patients. Additionally, according to clinical research, this combination has proved to be well tolerated and effective in the management of acute back pain disorders [24, 25].

It is noteworthy that the study results align with other investigations showing that B vitamins, specifically thiamine, pyridoxine, and cyanocobalamin, can act as an analgesic complement, potentially allowing for a reduction in the required daily doses of NSAIDs such as dexketoprofen and other anti-inflammatory drugs, thereby potentially minimizing the associated adverse effects. These findings seem to confirm the notion that B vitamins, while unable to produce anti-hyperalgesia directly, can enhance the anti-inflammatory activities of NSAIDs [12, 26]. In addition to this, it is important to highlight that previous studies confirm that the use of a single dose of dexketoprofen in acute pain achieved a similar analgesia level than that obtained with double doses of ketoprofen, particularly in moderate and severe pain, revealing an important reduction in VAS scores and a lower opioid consumption. Furthermore, in the review carried out by Kuczyńska et al., dexketoprofen exhibited a more prominent analgesic effect than acetaminophen and diclofenac, and fewer adverse effects compared with ketoprofen, aceclofenac, and naproxen [27,28,29]. Therefore, regarding pain intensity, the results for the FDC of dexketoprofen/vitamin B were observed above those reported by the literature for pain in cervical and low back disorders, with a decrease in VAS scores of − 1.5 cm (− 15/100 mm) after 24 h of treatment and a percentage change of − 20.3%, reaching a reduction of − 5.8 cm (− 58/00 mm) at 7 days of intervention and a final percentage change of − 79.6%. This evidence shows that a minimal clinically important difference in pain intensity can be considered from a reduction of 10/100 mm (1/10 cm) in the VAS scores or a total change of − 10 to − 20% [30], while a substantial improvement in the patient can be considered with scores of − 20 to − 27 mm (2.0–2.7 cm) or a total change of ≥ 50% [31].

Moreover, the observed potential reduction in NSAID consumption with the addition of B vitamins presents a compelling argument for considering these vitamins as adjuvants to conventional pain management strategies. This reduction is of extreme importance given the documented risks associated with NSAID treatment, particularly in terms of gastrointestinal and cardiovascular events [18]. The study suggests that measures leading to a decrease in NSAID dose and duration may contribute to mitigating these risks. Treatment with this combination has been associated with a significant improvement in pain scores and symptoms, considered as two of the main objectives for the management of pain conditions [32].

The main limitation of this study is related to generalizing the findings; since the study was oriented towards neck pain, it might not be directly applicable to chronic pain or other pain conditions. Chronic pain often involves complex mechanisms and the efficacy of the FDC of dexketoprofen/vitamin B in such contexts remains uncertain. The study had an appropriate randomization and blinding process, guaranteeing an adequate execution of the clinical study and follow-up of the included patients. This was reflected in a very low percentage of withdrawals during the development of the study. Studies with a longer follow-up period should be carried out.

5 Conclusions

This study provides evidence supporting the efficacy and safety of the FDC of dexketoprofen/vitamin B in the management of grade I–II cervical sprains. The FDC therapy demonstrated superior outcomes in terms of pain relief and reduction in disability compared with dexketoprofen monotherapy. These findings, along with the existing information, highlight the potential benefits of B vitamins (thiamine + pyridoxine + cyanocobalamin) as adjuvants to NSAIDs, not only in enhancing analgesic effects but also in potentially reducing adverse effects associated with prolonged use of NSAIDs.

Future clinical studies should further explore the use of B vitamins as analgesic adjuvants in various pain conditions, emphasizing the potential for reducing daily doses of NSAIDs and other anti-inflammatories, along with the approach on safety considerations. The current study provides valuable information on the multiple benefits of combining B vitamins with NSAIDs to improve pain management and patient outcomes.