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Material and methods

The study involved 70 patients with severe nonspecific pain syndrome in the lower back with an average VAS pain score of 4 or more and duration of up to 14 days. Back pain was defined as pain of appropriate intensity, located at the level between the lower part of the shoulder blades and the gluteal folds.

The study did not include patients who had specific pain in the lower back (due to injury, tumor, inflammatory and infectious lesions of the spine and other causes - spondylolisthesis, osteomalacia, arthritis, metabolic, osteoporosis, myelopathy, neuropathic pain syndrome caused by complex regional pain syndrome , neuralgia of peripheral nerves (intercostal, trigeminal nerve), with a history of diabetes mellitus, decompensation of somatic and neurological diseases, any serious illness (including systemic, oncological, psychiatric) or unstable medical condition leading to a significant limitation of life expectancy or making it difficult to perform protocol, a history of abuse or dependence on alcohol or other psychoactive substances within the last 2 years; pregnancy and lactation, as well as patients who, in the opinion of the investigator, could not perform the procedures within the study, the presence of possible allergic reactions to the components of the drug, as well as participation in another clinical or observational study currently or within 6 months before inclusion in the study, taking drugs or dietary supplements containing nucleotides 2 months before the patient was included in the study.

The patient was included in the study after the doctor made a decision on the advisability of prescribing the dietary supplement Neurouridine (for patients requiring standard drug therapy (NSAIDs, muscle relaxants, B vitamins)). Patients of the main group simultaneously with standard therapy received the dietary supplement Neurouridine in a dosage of 1 capsule per day. The course of treatment was 20 days. The comparison group received only standard therapy with NSAIDs and high-dose vitamin complexes. Patients were randomly selected for the open-label study.

The main group was represented by 50 patients, 46% men, average age 44±15 years. The comparison group consisted of 20 patients, 70% men, average age 46±11 years. Thus, in terms of age characteristics, both groups were comparable to each other.

To achieve the objectives of the study, a clinical method (anamnestic method, somatic and neurological examinations), as well as a clinical questionnaire and questionnaires were used. The questionnaire and questionnaires were an integral part of the patient’s individual registration card. The individual patient registration card included a passport part, a questionnaire part, and a section of specific questionnaires. The passport part consisted of data on body mass index, concomitant diseases and methods of their treatment (drug and non-drug), including those obtained at the time of the study. Anamnesis was collected to exclude patients who potentially did not meet the inclusion criteria for the study. Neurological and somatic status was assessed to exclude specific causes of back pain. Data were collected on the severity of the primary pain syndrome at the first and subsequent visits (visit 1 on the day of examination and dispensing of the drug, subsequent visits after 20 (visit 2) and 30 (visit 3) days).

Quantitative assessment of pain was made using a visual analogue scale (VAS), to fill which the patient was asked to rate the intensity of pain from 0 to 10 points, where 0 points is no pain, 10 is the worst pain ever experienced. In addition, a number of specific questionnaires were used:

— Pain Detect — the questionnaire most fully reflects all possible pain parameters and allows you to visually monitor the dynamics of the pain syndrome. Its sensitivity is 83%.

— The McGill questionnaire includes 3 scales: sensory (list of pain sensations), affective (impact of pain on the psyche) and evaluative (assessment of pain intensity).

- STarT Back Tool - a questionnaire consisting of 9 statements with which the patient is asked to agree or disagree, while the total score that the patient receives determines the prognosis of this pain syndrome - how much it can reduce the patient’s quality of life and ability to self-care (low risk, medium or high).

— Limitation of the patient's daily activities that is associated with pain was assessed at visits 1, 2, 3 using the Roland-Morris questionnaire completed by the patient. The Roland-Morris questionnaire is a widely used instrument for collecting data directly from the patient that assesses pain-related functional status. The Roland-Morris Questionnaire includes 18 statements about pain-related limitations in daily activities. The overall score ranges from 0 to 18 points; a higher score corresponds to a higher level of pain-related activity limitation. To obtain the final score, all marked items were summed up.

Due to the high comorbidity of pain syndrome with sleep disorders - both pre- and intrasomnic - one of the points of interest was to assess how pain syndrome and its reduction indirectly affect sleep quality. To identify sleep disorders, we used the Pittsburgh Sleep Quality Questionnaire (PSQI), which contains 11 blocks of questions with long and short answers, which in detail allow us to identify problems with late falling asleep and sleep-wake disturbances, sleep maintenance disorders (awakenings, total sleep time, associated symptoms : snoring, anxiety), provide information about possible pre-, intra-, post-somnic disorders, and the use of hypnotics.

To identify anxiety and depressive disorders, the Hospital Anxiety Depression Scale (HADS) was used, which also consists of 2 sections, each of which is responsible for identifying anxiety or depressive disorders. The patient is offered 14 statements, some of which describe depressive symptoms, some - anxiety, the choice of severity and significance of each item is assessed on a 3-point scale. On this scale, indicators of 7 points or less are considered normal; with values of 8-10 points, anxiety or depression are regarded as subclinical; 11 points and above are considered clinically pronounced.

Further during therapy, at visits 2 and 3, the patient global impression (CGI) scale of satisfaction with therapy, as well as the clinical impression of the treating physician, was used.

In addition, safety data were analyzed - side effects on the therapy were assessed in both groups.

The work was carried out on the basis of Scientific Research Medical LLC (Kazan). The study received approval from the Local Ethics Committee of NIMK Your Health LLC. All patients signed informed consent to participate in the study before starting the study.

Spreadsheets and the statistical analysis program IBM Statistics SPSS 20.0 were used to evaluate, analyze and obtain results. In the initial assessment of the main criterion, the distribution can be considered normal and parametric data analysis tools can be used: average values, using the concepts of standard deviations and Pearson tests, McNemar test, a posteriori Wilcoxon signed rank test for paired samples.

results

When analyzing the data, the following results were obtained: 26% of patients from the main group had various forms of comorbid pathology (arterial hypertension, chronic bronchitis, gastrointestinal pathology, etc.). However, due to the significant scatter of data on these indicators and the relatively small contingent of subjects examined, it was not possible to conduct any correlations on these indicators.

It should be noted that the patients were very heterogeneous in a number of other parameters: profession, physical activity, bad habits, body mass index, which, in particular, ranged from 18.9 to 38. From the point of view of the concept of the biopsychosocial model of pain, all of the above components have absolute significance for the formation of a pain syndrome, but in the case of this observational clinical study, it was not possible to form a single “portrait of a patient with pain.”

Assessing the dynamics of pain was extremely important. All patients included in the study had pain according to the VAS scale of at least 7 points, which indicates its significant intensity. Pain syndrome was assessed at all three visits, thus, this assessment method made it possible to track the dynamics of its reduction in different groups. The average VAS score of patients at visits 1, 2 and 3 is presented in Table. 1 . The severity of changes in condition at different visits over time was assessed using the McNemar test (level of effectiveness in the main group p>0.0001, in the comparison group - 0.001) with two-sided significance.

Table 1. Average VAS score of patients at visits 1, 2 and 3

Group	Visit 1	Visit 2	Visit 3	Difference between visits 1 and 3	Difference between visits 1 and 2
Main, n=50	7,9±2,3	3,3±1,9	1,2±1,2	6,7±1,8	4,6±2*
Comparisons, n=20	7,4±1,4	4,74±2,4	1,37±1	6,03±2,3	2,66±1,1

Note. Here and in the table. 2 : *—statistical significance at p<0.05 level.

By visit 3 (after 20 days), with a significance of more than p<0.001, all those examined in both groups noted an improvement in their condition. But at the same time, attention is drawn to the fact that in the main group after 10 days of therapy there was a more pronounced positive dynamics of the pain syndrome, so the difference in VAS pain between visits 1 and 2 in the main group was 4.6±2 points (p<0. 05), and in the comparison group - 2.66±1.1 points.

When analyzing clinical data together with test results in 32% of patients from the main group, a detailed analysis revealed the phenomenon of the addition of varying degrees of severity of the neuropathic component of pain, despite the fact that the study did not include patients with obvious signs of compression radicular syndromes.

An analysis was carried out for each of the questionnaires separately, as well as over time and for group comparison. The average value of the Pain Detect scale in the main group from visit 1 to visit 2 (before and after treatment) decreased from 11.9±8 to 2.6±3 points (p<0.0001).

In the comparison group, this indicator was 8.1±4 and 3.91±2 points with the same level of evidence, despite the greater pain intensity in the initial state. Thus, we can conclude that there was a greater degree of reduction in pain intensity in the main group than in the comparison group (Fig. 1) . It should be noted that the high scores on this questionnaire in the main group may be explained by the fact that the study was open in nature and doctors included patients with a more severe course of the disease and a higher intensity of pain in the group of people receiving the dietary supplement Neurouridine.

Rice. 1. Indicators of the Pain Detect questionnaire at visits 1, 2 and 3 (points).

The level of decrease in the severity of neuropathic pain, according to the Pain Detect test, in the main group (11.9 to 2.12 points) compared to the comparison group (from 8.1 to 2.3 points), allows us to talk about the impact on the neuropathic component pain in such patients (p<0.01).

Analysis of the STarT Back Tool scale revealed a pronounced reduction in the risk of developing disability in both groups (p<0.01). A post hoc Wilcoxon signed rank test for paired samples indicates a more pronounced reduction in pain in the main group (two-sided significance at p<0.01).

The average Roland-Morris score of patients in the main group at visits 1, 2 and 3 and the comparison group is presented in Table. 2 .

Table 2 . Average Roland-Morris score of patients at visits 1, 2 and 3

Group	Visit 1	Visit 2	Visit 3	Difference between visits 1 and 3	Difference between visits 1 and 2
Main, n=50	13,5±3,2	6,4±2,3	2,5±1	11±3,1*	7,1±1,9
Comparisons, n=20	10,79±2,5	3,93±0,8	1,16±0,2	9,63±2,4	6,86±1,3

Improvement by visit 3 was noted in 100% of cases with a significance of p<0.001.

The variable for which the f-test also corresponds to the established significance level of 0.05 is the Roland-Morris Questionnaire (Visit 1), for which the p-level is 0.043. As presented in the graph, the columns show average values, but for the main group this variable takes on average significantly higher values - on the selected measurement scale for the comparison group it is equal to 9.7, and for the main group - 11.3 (Fig. 2) . This illustrates the fact that the group of patients who received the dietary supplement Neurouridine as an additional therapy included patients with a more severe course of the disease, and it should be emphasized that, despite the obvious fact of a decrease in scores on the Roland-Morris questionnaire in both groups, in patients who received additional therapy and had worse results on this questionnaire initially, we see more pronounced dynamics of improvement in well-being, i.e. with higher “starting” numbers for this test, when patients reported a significant deterioration in their functional status, its dynamics during treatment were more noticeable.

Rice. 2. Average values of the Roland-Morris questionnaire (along the ordinate) in groups (a - main group, b - comparison group).

When comparing the patient's overall impression and satisfaction with treatment, it was found that in patients of the main group who additionally took Neurouridine, satisfaction with treatment was higher. In the main group: by visit 3, 60% of patients noted 5/5 satisfaction with treatment, 33% - 4/5, 7% - 3 or less, and in the comparison group - 20%, 70% and 10, respectively (Fig. 3) .

Rice . 3. Patient satisfaction with the results of the treatment received at visit 3 (%).

Thus, in the main group at visit 3, most of the patients noted complete satisfaction with the therapy, while in the comparison group, most of them noted an improvement, but incomplete. This indicates a more pronounced effect of therapy in the main group.

The McGill questionnaire in this study did not reveal any significant differences in the groups, which allows us to indirectly conclude that the Pain Detect questionnaire is more sensitive in the groups of individuals examined.

Evaluation of the HADS scale showed that in patients receiving additional therapy with the dietary supplement Neurouridine, the difference in average scores was 1.5 points lower than in the comparison group (Fig. 4) . Of course, this value may not be regarded as a statistically accurate result (which may be due to the short period of treatment, because it is known that even in the case of prescribing anxiolytics and, especially, antidepressants, the “response” to therapy occurs in the 3-4th week treatment), however, to a certain extent, the data obtained give an idea of the trend in the change in the indicator and inspire some optimism for subsequent research in this direction.

Rice. 4. Dynamics of anxiety indicators on the HADS scale (points).

Sleep disturbances using the χ2 method and the Pearson correlation coefficient predominantly provide correlation indicators with the intensity of pain according to VAS and overall satisfaction with therapy. A direct correlation was also revealed between a decrease in pain intensity according to VAS and a reduction in sleep disturbances according to PSQI (Fig. 5) . In the main group, the improvement was 1±2.4 points, with the significance of the paired samples test at the level of p<0.034 relative to visit 2, the improvement in indicators in the comparison group averaged 1.3±2 points, a two-sided significance of the improvement at the level of p<0.01 .

Rice. 5 . Indicators of pain intensity scales (VAS) and PSQI scales in the main group at visits 1, 2, 3 (points).

The study did not reveal any side effects associated with taking the dietary supplement Neurouridine. In both groups, there were cases of moderately severe dyspeptic disorders (mainly heartburn - 3 cases, pain in the epigastric region - 2 cases), which, in our opinion, was associated with the use of NSAIDs, and their frequency did not go beyond the statistical error.