NEUROPATHIC PAIN IS AN INDEPENDENT PREDICTOR OF WORSE QUALITY OF LIFE IN PATIENTS WITH DIABETIC NEUROPATHY NEUROPATSKI BOL KAO NEZAVISAN PREDIKTOR LOŠIJEG KVALITETA SA DIJABETESNOM NEUROPATIJOM

Introduction/Aim:The aim of this study was to examine influence of neuropathic pain on quality of life (QoL) in patients with diabetic sensorimotor polyneuropathy (DSPN) who did not have neither another diabetic complications nor any other significant comorbidities. Methods: Thirty two patients with DSPN and definitive neuropathic pain were compared with 32 patients with DSPN without neuropathic pain matched for age, gender, and duration of illness. Following scales were used: Pain Detect Questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropatathique en 4 Question, Hamilton depression and anxiety rating scales, Neuropathy Impairment Score of the Lower Limb (NIS-LL), and SF-36 questionnaire. Results: Patients with neuropathic pain had significantly more severe DSPN measured with NIS-LL (p<0.01). Also, they were more likely to be engaged in physical work (p<0.05), and had more depression (p<0.05) than patients without neuropathic pain. Patients with neuropathic pain had significantly lower QoL in both physical and mental domains (p<0.01). Independent predictors of worse QoL in DSPN were presence of depression (beta=-0.58, p<0.01) and presence of neuropathic pain (beta=-0.23, p<0.05) - R 2adjusted =0.48. Conclusion: Independent predictors of QoL in patients with DSPN were presence of depression and neuropathic pain, which signifies importance of early recognition and early treatment of these symptoms.


INTRODUCTION
Neuropathic pain is, as defined by the International Association for the Study of Pain (IASP), a pain that arises as a direct consequence of the lesion or disease of the somatosensory system (1). According to the site of the lesion, it can be peripheral (lesions of peripheral nerve, nerve plexus, dorsal ganglion, nerve root) and central (lesion of the spinal cord or the brain) (2). Peripheral neuropathic pain is significantly more common and better studied than central neuropathic pain, and its most common cause is diabetic polyneuropathy (DPN). The most common form of DPN is chronic, symmetrical, lenghtdependent sesorimotor polyneuropathy (DSPN), observed in 30-50% of patients with diabetes mellitus (DM) (3). Taking into account that the prevalence of diabetes in general population is above 8% and that it is constantly increasing, number of diabetic patients with neuropathic pain is large (4). In the United States prevalence of diabetes in 2017 was even 9.3% (5).
It has been shown that DPN reduces quality of life (QoL) (6,7). In addition, even patients with subclinical forms of DPN may have reduced QoL (8). Numerous studies on QoL in patients with DPN were conducted, but they usually included patients who had other significant complications of diabetes or other associated comorbidities that also could strongly affect QoL (7,9,10). Also, in many of these studies patients were included although they did not have diagnosis of definite DPN, assessment of neuropathic pain in these studies has not been consistent, and some patients even used neuropathic pain medication and antidepressant drugs.  (11) and diagnosis of definitive DSPN in accordance to criteria proposed by Dyck et al (12). Fifteen patients were excluded due to comorbidities including history of stroke, and myocardial infarction, heart failure, renal faliure, and limb amputation. Patients who abused alcohol, or use neuropathic pain medication or psychiatric therapy were also excluded.
We used three questionnaires for the diagnosis of neuropathic pain (the Pain Detect Temperature of the tested limbs was above 31ºC. NCS were conducted using superficial stimulation and registration electrodes. Motor conduction velocity (MCV) (median, ulnar, peroneal and tibial nerves) and sensory conduction velocity (SCV) (median, ulnar and sural nerves) were examined. Also, we tested the amplitudes of the compound muscle action potentials (CMAP) and minimum F-wave latency for previously mentioned motor nerves and amplitude of the sensory nerve action potentials (SNAP). 21-item Hamilton depression rating scale (Ham-D) was used to assess depression where score >8 indicates the presence of depression (17). Hamilton anxiety rating scale (Ham-A) was used to estimate anxiety, where score >18 indicates the presence of anxiety (18). As a measure of health-related QoL, each patient filled in the Serbian version of the  questionnaire (19) which is a generic measure that combines eight general health concepts: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH).
Besides the total SF-36 score, physical composite score (PCS) and mental composite score (MCS) are two main scores to summarize these eight scales. All scores are interpreted with a 0-100 scale, where higher numbers represent better QoL.
Statistical data processing was performed in SPSS version 17.0 (SPSS Inc., Chicago, Illinois, USA). All examined variables were first analyzed using the Kolmogorov-Smirnov test to determine whether they were distributed by normal distribution. For the comparison of nominal and ordinal variables, the χ 2 test or Fisher test were used. Difference between two continuous non-parametric variables was investigated using the Mann-Whitney U test, while Student's t test was used for continuous parametric variables. All variables that differed between patients with and without neuropathic pain were included in the multiple linear regression analysis (stepwise method) as independent variables, while SF-36 score was considered dependent variable. Level of statistical significance was 0.05 for statistically significant difference and 0.01 for highly statistically significant difference.

RESULTS
Sociodemographic and clinical characteristics of our cohort of patients are shown in Table 1. Patients with neuropathic pain had significantly more severe form of DSPN measured with NIS-LL scores (p<0.01), and were more likely to be engaged in physical work than patients without neuropathic pain (p<0.05). Other parameters did not differ.
Results of psychological status assessment are shown in Table 2. Patients with neuropathic pain had a significantly higher score on depression scale and a higher percentage of depressed patients compared to the patients without neuropathic pain.
Results of QoL assessment are shown in Table 3. All SF-36 domains were significantly worse in patients with neuropathic pain, except for RE. Patients with neuropathic pain also had significantly lower PCS, MCS, and total SF-36 scores.
In multiple linear regression analysis (stepwise method), we included all variables that differed between patients with and without neuropathic pain (presence of neuropathic pain, 8 NIS-LL total score, occupation and results on Ham-D) ( Table 4). Presence of neuropathic pain and presence of depression appeared as independent predictors of poor QoL in DSPN.

DISCUSSION
The results of our research showed reduced QoL in patients with DSPN, especially in those with neuropathic pain. This means that treatment of neuropathic pain may significantly improve QoL of these patients, particularly because there is no effective causative therapy for polyneuropathy. In our group of patients with neuropathic pain compared to those withount neuropathic pain, much lower PCS, MCS and total SF-36 scores were observed. Furthermore, the study showed that all QoL domains (except RE) were significantly worse in patients with neuropathic pain. We demonstrated that neuropathic pain was an independent predictor of poorer QoL in patients with diabetic neuropathy.  (20,21). Such a good result for PF in our patients is due to the fact that DSPN is predominantly sensory polyneuropathy in which motor fibers are long preserved and that patients with significant comorbidities were excluded. On the other hand, different results were obtained in another studies that found PF to be among the worst scores (9,10,22). It is of note that patients with significant comorbidities were included in these studies which certainly may affect the results.
The worst results on SF-36 were obtained for GH in both investigated groups of patients, which is a score where patients directly estimate and anticipate their health and 9 diseases. These findings correspond to the results in most of the studies published so far, in which it was found that this item was among the most commonly and severely affected on SF-36 scale (9,10,20,21). RP was a subdomain with very low scores in patients with neuropathic pain, and very high in patients without neuropathic pain. Similar results were found in other studies which suggest significant influence of neuropathic pain on patients' working ability and other daily activities scale (9,10,20,21). It also should be mentioned that our patients with neuropathic pain more frequently performed physical than intellectual job. So, it is possible that neuropathic pain has impact on their working ability and vice versa.
Our patients with neuropathic pain had more severe form of neuropathy since they Linear regression analysis showed that the presence of depression and neuropathic pain were predictors of worse QoL in patients with DSPN and that the obtained model explained almost 50% of the total SF-36 score variance. It is of note that there are another factors not included in our analysis that could explain remaining 50% of the variance. Previous studies showed that the most important predictors of QoL in diabetic patients with or without neuropathy are associated with disease itself rather than with sociodemographic factors (27,28), while the presence of macrovascular complications is the most important predictor as was noted in a review article (29). In a prospective study of 53 patients with DSPN in DM type 2, Lyracos et al. found that QoL was significantly reduced compared to the general population, and the most important predictors of QoL were: symptoms and signs of diabetic polyneuropathy measured by the Michigan Neuropathy Screening Instrument, HgbA1C level, reduction of activity, mental fatigue, depression, neuropathy treatment and the presence of cardiovascular diseases (27). Papadoupolos et al. found that significant predictors of QoLwere female sex, complications of diabetes, other associated diseases not related to diabetes, duration of diabetes (28).
Main limitation of our study is a relatively small sample size. The strength is in fact that the research involved patients who had a confirmed DSPN diagnosis and a definitive diagnosis of neuropathic pain, and that control group of patients with DSPN without neuropathic pain was also included. In addition, we included only the patients with no other significant complications of diabetes or comorbidites that could affect QoL.

Conclusion
We found significantly lower QoL in both physical and mental domains in patients with DSPN and neuropathic pain compared to patients with DSPN without neuropathic pain. Independent predictors of QoL in patients with DSPN were presence of depression and neuropathic pain, which signifies importance of early recognition and early treatment of these symptoms.