Introduction

Globally, Lumbosacral Radicular Syndrome (L.R.S.) is among the most prevalent issues affecting the lumbar spine, significantly reducing the quality of life for patients and is one of the most encountered pathologies in primary care [1]. It is noted that approximately 3 to 5% of adults will encounter L.R.S. during their lifetime [2,3], serving as a primary contributor to prolonged disability [4], absenteeism from work, and increased utilization of long-term healthcare services with corresponding costs [5]. Lumbar Disk Hernia (L.D.H.), degenerative spondyloarthropathies, or lumbar spinal stenosis, including Lateral Recess Stenosis (L.S.S.), are frequent causes of L.R.S. [1,6,7]. Validated instruments indicate that the rate of radiculopathy resulting from lumbar disk prolapse is between 17% and 50% [8]. A clinical examination aims to identify common symptoms, such as radiating pain frequently accompanied by numbness, paraesthesia, and/or muscular weakness, and to determine if a nerve root has been mechanically impinged upon [9,10]. A neuropathic component of pain is often present in 36% to 55% of patients with spinal diseases, including L.R.S. Regarding mechanism, neuropathic pain syndromes are defined by the maladaptive plasticity of neurons, immune cells and neuroimmune inter-actions throughout the pain pathway, the causative mechanisms of which remain in-completely understood [11,12].

After a complete assessment of the L.R.S. patient, a complex rehabilitation program will be applied to regain and maintain the patient’s quality of life and well-being. Treatment options for L.R.S. are diverse and may encompass medication as well as physical and kinetic programs (physiotherapy interventions are prescribed as first-line treatment, but their effectiveness remains controversial) [13] or surgical decompression (suggested for patients experiencing persistent symptoms such as progressive/ severe neurological impairment, including cauda equina syndromes, and/or enduring pain) [14,15]. The primary tasks in assessing and managing L.R.S. are to exclude signs and/ or symptoms of possible underlying severe pathology, focus on an active approach to promote natural recovery, and prevent chronicity through early tailored rehabilitation [16].

Typically, the selection of therapy involves integrating clinical recommendations with the unique status of the individual patient [17,18]. There is consensus (systematic reviews and clinical practice guidelines) that the first six to eight weeks of L.R.S. therapy should be conservative [19]. However, it’s unclear precisely what the conservative approach entails at this point [20,21]. Recent research has highlighted the potentially complex roles of B vitamins in the maintenance of nervous system function, and deficiencies of which may result in peripheral nervous system disorders, as an adjunct to NSAID therapy, or in the treatment of neuropathic pain and symptoms of neuropathic conditions [22-26]. It has demonstrated the effectiveness of administering medications containing pyrimidine nucleotides (uridine triphosphate – U.T.P., cytidine monophosphate - C.M.P.) in reducing pain intensity associated with diabetic neuropathy, back pain, cervical pain, and trauma-compressive disorders [27], with neuro regenerative properties in the medium term [28]. The use of uridine and cytidine nucleotides associated with hydroxocobalamin had positive control of the intensity of chronic neuropathic low back pain, with a reduction in the consumption of rescue analgesics, thus improving and enhancing the quality of treatment [27,29], and in reducing the pain and improving the motor activity of the patients with alcoholic polyneuropathy [30]. Another combination - uridine monophosphate, folic acid, and hydroxycobalamin has been controlled in pain for patients with peripheral neuropathy and neuropathic pain and reduced the adjunctive use of analgesic or anti-inflammatory drugs [31].

Despite its classical role in calcium and phosphorus metabolism, vitamin D plays a vital role in the etiology and progression of various chronic pain conditions and associated comorbidities by exerting anatomic, hormonal, neurological, and immunological influences on pain expression [32,33]. This vitamin is involved in modulating neuroinflammation, maintaining neuroplasticity, and expressing neurotrophins in various physiological and pathological contexts. In the adult brain, vitamin D has both genomic and non-genomic actions on various neurological functions [34].

Taking into consideration all these recent studies, we performed a prospective study. We analyzed the effects of ProHumano+ SpineDinamic (PHSD) on reducing the severity of radicular pain and improving the quality of life in patients with L.R.S. over a three-month period. PHSD is a complex of nucleotides and vitamins B1, B6, B12, and D3, manufactured and supplied by PharmaLinea Ltd. (Ljubljana, Slovenia). The effectiveness of this product in controlling the clinical-dysfunctional status of patients with L.R.S. has yet to be studied. By combining nucleotides, vitamins B1, B6, B12, and D in a single tablet at the optimal dose, with the summation of the therapeutic effects of each vitamin, easy to ad-minister, we tried to prove the product’s effectiveness in conditions of increased compliance.

Materials and Methods Ethical approval

Before being included in the study, the details of the present research were explained to the patients. Written informed consent was obtained from each patient. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices and was approved by the local independent ethics committee (approval no. 9057/ 3rd May 2022).

Study Design

Our prospective, double-blind, randomized study was conducted in the Departments of Physical Medicine and Rehabilitation, Filantropia Hospital, Craiova, and Techirghiol Balneal and Rehabilitation Sanatorium from June 2022 to October 2022. Prior to the study, the clinical-paraclinical evaluation protocol and the rehabilitation program were established in agreement with the specialists from the two centers. Therefore, there were no differences in approach.

A total of 300 patients with L.R.S. lasting more than three months were enrolled in this study, with a 2:1 ratio between the treatment groups. All patients have been previously diagnosed with L.D.H., degenerative spondyloarthropathies, or L.S.S. The study blinded both patients and investigators. Randomization was generated using the medication code, made by an independent physician.

Following the initial evaluation, 247 patients were randomly allocated into two groups: Group 1 (G1) underwent ten sessions of a rehabilitation program along with PHSD (daily, for three months), while Group 2 (G2) underwent ten sessions of a rehabilitation program along with a placebo (daily, for three months) (Figure 1).

Figure 1: Diagram of our study.

The patients were included in the study in the order of presentation at admission. After the diagnosis, each patient was given a tablet without him or the attending physician being informed about the meaning of the code on the received tablet. The placebo and PHSD forms were identical but with a different code on the packaging. The rehabilitation program was carried out by an independent physiotherapist. The study team was the only one that grouped the patients, according to the diagram.

Each PHSD capsule contained 75.3 mg of Qspine^® complex. Qspine^® is a proprietary complex consisting of nucleotide complex and vitamins B1, B6, B12, and D3. Starch-based placebo products matched the size and weight of PHSD capsules to maintain blinding. Both products were developed, manufactured, and supplied by PharmaLinea Ltd. (Ljubljana, Slovenia). All subjects were instructed to take one capsule per day.

Conventional physical therapy (transcutaneous nerve stimulation, ultrasound, and low-intensity laser treatment) and kinetic program (stretching and postural control, lumbar strengthening, and stabilizing exercises) represented the components of the re-habilitation program performed by all patients.

All patients were followed daily for ten days, with the electrotherapy session in the morning and the kinetic program in the afternoon. The electrotherapy session included the three procedures applied at the lumbosacral level. The parameters for each procedure were those for analgesia, with a duration of 15 min for transcutaneous nerve stimulation, 10 min for ultrasound, and 5 min for low-intensity laser treatment.

The kinetic program had a duration of 30-40 minutes. Initially, it was applied passively so that the patient could learn the movement correctly, and later, it was actively assisted. Stretching was carried out for the paravertebral muscles, hamstrings, and adductors of the rib, as well as toning for the abdominal muscles and gluteus medius muscle. Postural control was achieved through walking and coordination exercises for the lower body. Inclusion and exclusion criteria are mentioned in Table 1.

Table 1: Inclusion and exclusion criteria.

The study included two visits: pretreatment (Visit 1 / T1 - initial) and after three months (Visit 2 / T2 - final). These specific time points were selected to gauge the rate of improvement across all outcome measures effectively.

Patient’s assessment

A precise evaluation of L.S.R. patients is essential to deliver appropriate management and treatment promptly upon initial presentation [35].

So, each study visit consisted of a clinical and functional assessment, vital signs measurement, and laboratory testing. After careful anamnesis (age, comorbid diseases), the clinical assessment included:

• General physical examination (body mass index – B.M.I.);
• musculoskeletal and neurological assessment involves a somatotopic examination, systematic palpation of all regions of the vertebral column, evaluation of range of motion (such as finger-to-floor distance - FFD, measured and recorded in centimeters; Schober test), assessment of tenderness and stability, manual muscle testing of the trunk and lower limb muscles, chronic lumbar root irritation and dysfunction (including straight leg raise - S.L.R. test, identification of radicular syndrome symptoms such as sensory loss, weakness, pain location, reflex loss, and myofascial syndrome);
• Evaluation of equilibrium and walking pattern (tip-toe walking).

During the examination, we conducted standard laboratory tests (screening, inflammation tests – fibrinogen and C reactive protein) and imagistic examination of the lumbar column (radiologic and M.R.I. exams).

The functional evaluation included:

• the VAS - Visual Analogue Scale (from 0 to 10, 0 = absence of pain and 10 = maxi-mum pain score; other values between 0 and 10 are directly proportional to the intensity of pain, depending on the individual pain threshold);
• The short-form McGill Pain Questionnaire (SF-MPQ) - a comprehensive tool for evaluating pain, comprising a sensory subscale with 11 items and an affective subscale with four items. Each item is rated on an intensity scale ranging from 0 (none) to 3 (severe) [36].
• the Katz Index of Independence in Activities of Daily Living (A.D.L.) - the most appropriate instrument to assess functional status as a measurement of the patient’s ability to perform activities of daily living independently (the six functions of bathing, dressing, toileting, transferring, continence, and feeding are scored yes/no). A score of 6 indicates full function, 4 indicates moderate impairment, and two or less indicates severe functional impairment [37,38].

Safety was evaluated through the occurrence of adverse reactions throughout the treatment period.

Statistical analysis

Statistical analysis was performed using Microsoft Excel (Microsoft Corp., Redmond, WA, U.S.A.), together with the XLSTAT add-on for M.S. Excel (Addinsoft SARL, Paris, France). Data were recorded using Microsoft Excel files, and then it was statistically analyzed to find the relationship between the variables of interest for the two groups of patients.

To assess the normality of the data, we employed the AndersonDarling and Shapiro-Wilk tests. Given that the data from the study did not follow a normal (Gaussian) distribution and involved numerical comparisons between two groups of patients, we predominantly utilized the nonparametric Mann-WhitneyWilcoxon test instead of Stu-dent’s t-test to identify significant differences among the values in the compared data sets.

We also used the nonparametric Spearman’s rank correlation test to measure the strength of association between two ranked variables.

Results

We included a total of 247 LRS patients in our study; all patients followed the same re-habilitation program, but only 151 patients were treated with PHSD (G1). The remaining 96 patients received placebo treatment (G2).

Females and urban patients were dominant in both groups. Most patients were over-weight and between 50 and 79 years old (mean value - 61.33 years for G1 and 62.44 years for G2). All patients had chronic pain and a disability status of their A.D.L.s.

After the initial evaluation of the patients, the finalization of the two groups resulted in an unequal number of patients for the two groups. Although unequal in number, the two batches are homogeneous in the distribution for biographical data, maintaining a ratio of 1.5 (Table 2).

Table 2: Demographic parameters of patients.

For none of the analyzed qualitative variables, socio-demographics, or related to the history of the condition, we did not identify distribution differences between the two groups. Therefore, the two groups are perfectly compatible from the point of view of gender distribution, residential environment, age, profession, previous rehabilitation, and weight status (B.M.I.).

We noted a significant difference between G1 and G2 for B.M.I. in both moments of evaluation (Figure 2). In T1, the mean value (S.D.) was 28.57 (5.53) for G1 and 29.65 (5.07) for G2; in T2, the mean value (S.D.) was 28.34 (5.27) for G1 and 29.54 (4.89) for G2. These average values of B.M.I. were located in the overweight interval, which means that our patients were not obese but did not fit into the normal weight range.

Figure 2: Body Mass Index - B.M.I. (kg/m²) values in T1 (initial) and T2 (final) evaluation moments.

We prescribed a rehabilitation program (physiotherapy and kinetic program) as first-line management in L.R.S. Because physiotherapy and kinetic interventions are less effective in reducing pain at the medium term and disability at short- and medium-term time points, as mentioned in medical data [13], pain and functioning patients in G1 had been controlled with PHSD. No serious adverse events were reported during the study, so we have noted no treatment discontinuation in any of the groups.

In our study, patients in both treatment groups displayed significant improvement in all parameters in T2 compared to pretreatment status (T1) (Tables 3 and 4). With a few exceptions, the recorded variables did not follow a normal Gaussian distribution, as assessed with the Anderson-Darling normality test.

Vas scale from 7.60 to 4.65, Short-form McGill Pain Questionnaire (SF-MPQ) from 21.45 to 12.20, Katz Index of Independence in Activities of Daily Living (ADL) from 3.83 to 4.15, and Clinical assessment. We considered six clinical parameters to follow in our research. All values are mentioned in Table 3.

Table 3: Clinical parameters values in all studied patients.

Analyzing the differences between the values obtained between the patients from the two groups (Figure 3), we noticed that, for the T1 moment, there was a statistically significant difference only for the S.L.R. test (those from the G2 group having lower values, p Mann-Whitney=0.0029>0.05). At the T2, statistically significant changes between G1 and G2 were recorded for the Schober test (p Mann-Whitney=0.0004<0.001), radicular syndrome (p Mann-Whitney=0.0321<0.05), and myofascial syndrome (p MannWhitney=0.0237<0.05). In the straight leg raise test, G1 patients recovered more than those from G2, but the difference between groups didn’t reach statistical significance (p Mann-Whitney=0.4259>0.05).

Figure 3: The four out of six clinical parameters are values in the T1 (initial) and T2 (final) evaluation moments. Schober test - S.T., a finger-to-floor distance – FFD, manual muscle testing of the trunk – T.M.M., straight leg raise test - S.L.R., radicular syndrome - R.S., myofascial syndrome - M.S.

Within the group comparison between both time points revealed that a statistically significant difference was achieved in the finger-to-floor distance test for G1 (p test Wilcoxon<0.001), while the same group achieved better improvements in the Schober test, but the difference wasn’t significant (p Wilcoxon=0.1382).

Both groups scored highly statistically significant changes in the straight leg raise test (p test Wilcoxon<0.001), radicular syndrome (p Wilcoxon test<0.001), and myofascial syndrome difference (p test Wilcoxon<0.001). We consider the clinical relevance of the obtained results necessary for the category of patients studied. No other pharmaceutical products were administered to control the pain parameter, with the exception of Pro Humano+SpineDinamic. By reducing the pain status, the kinetic program was optimally performed, with a favorable clinical and functional impact.

The lab data was followed by other parameters studied. There were no significant differences in biochemical and inflammatory parameters between the groups. This aspect permitted the application of rehabilitation programs in safe conditions.

Functional assessment was performed with three scales, mentioned in Table 4. All patients had moderate impairment; the mean value of Katz Index of Independence in Activity of Daily Living (A.D.L.) was nearly 4, with mention that after three months of PHSD treatment, the value was 4.15.

Table 4: Functional parameter values in all studied patients.

Analyzing the differences between the values obtained between the patients from the two groups (Figure 4), we noticed that, for the moment T1, there was no statistically significant difference for any of the three parameters. By the T2, participants in G1 reached highly significant improvements in the VAS scale (p Mann-Whitney<0.001), SF-MPQ (p Mann-Whitney<0.001), and A.D.L. scale values (p Mann-Whitney=0.0183<0.05), when compared to patients in G2.

Within the group, the comparison revealed that both groups recorded highly significant differences through VAS (p Wilcoxon test<0.001) and SF-MPQ measurements (p Wilcoxon test<0.001). Only G1 reached a highly significant difference by T2 on the A.D.L. scale (p Wilcoxon test=0.0002<0.001), while for outcomes of G2, no significance has been found in the difference from T1 to T2 (p=0.1515>0.05).

Figure 4: Functional parameter values in T1 (initial) and T2 (final) evaluation moments. VAS SCALE = Visual Analogue Scale, MCGILL = the short-form McGill Pain Questionnaire (SF-MPQ), ADL SCALE = the Katz Index of Independence in Activities of Daily Living.

We analyzed the correlation between the imagistic aspects (X-ray and M.R.I.) and the functional parameters variables (VAS, SF-MPQ, A.D.L.) with the aid of Spearman’s correlation coefficient. The values in Table 5 represent Spearman’s rho coefficient of correlation.

Table 5: Correlation matrix (Spearman) / Group 1 and Group 2 / T1 and T2.