Coenzyme Q10 as a potential add-on treatment for patients suffering from painful diabetic neuropathy: results of a placebo-controlled randomized trial.

BACKGROUND: We hypothesized that the addition of coenzyme Q10 (CoQ10) to pregabalin might be helpful in improving symptoms in patients suffering from painful diabetic neuropathy (PDN). METHODS: One hundred twelve patients with PDN were randomly allocated to receive CoQ10 + pregabalin (57 patients) or placebo + pregabalin (55 patients). Besides pregabalin (150 mg/day), the patients, upon their group assignment, received CoQ10 at a dosage of 100 mg every 8 h or matched placebo for 8 consecutive weeks. The primary efficacy measure was the changes in the pain intensity from baseline to endpoint measured on an 11-point NRS (numeric rating scale). Secondary efficacy measures included the changes in the pain-associated sleep interference score (SIS) as well as the patients' global improvement with treatment measured on the Clinicians' and Patients' Global Impression of Change (CGIC/PGIC). RESULTS: On the intent­to­treat population (ITT) analysis, the CoQ10 + pregabalin regimen resulted in significantly greater pain relief than the placebo + pregabalin regimen. By the end of week 2, the decrease in the mean pain NRS score was similar in both groups, but at the end of weeks four and eight, the decrease in the mean pain NRS score was significantly greater in patients taking CoQ10 + pregabalin than in those taking placebo + pregabalin (p value = 0.01 and < 0.001, respectively). Likewise, at the end of week 8, the decrease in the pain-associated SIS was significantly greater in the patients supplemented with CoQ10 compared to placebo. Furthermore, the proportion of the responder patients (those having ≥ 50% decline in the mean pain NRS score) as well as the proportion of patients rated ''very much'' or ''much improved'' on the CGIC/PGIC scales were also significantly higher in the CoQ10 + pregabalin-treated patients than placebo + pregabalin-treated patients. CONCLUSIONS: Our data support the idea that diabetic patients suffering from PDN may benefit from using antioxidant and anti-inflammatory supplements like CoQ10. However, further studies are required before supplementation with CoQ10 can be recommended for treating PDN. TRIAL REGISTRATION: The trial was registered at Iranian Registry of Clinical Trials (identifier code: IRCT20120215009014N385). Registration date: 2021-02-21.

Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial.

PURPOSE: The trial aimed to investigate the effectiveness of exogenous melatonin as an adjuvant to pregabalin for relief of pain in patients suffering from painful diabetic neuropathy (PDN). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial was carried out between October 2019 and December 2020 in an outpatient specialty clinic in Iran. One-hundred-three type 2 diabetic patients suffering from PDN were randomized into either the melatonin group (n = 52) or the placebo group (n = 51). Besides pregabalin at a dose of 150 mg per day, patients started with melatonin or an identical placebo, at a dose of 3 mg/day at bedtime for 1 week, which was augmented to 6 mg/day for further 7 weeks. The primary outcomes were changes in mean NRS (numerical rating scale) pain score from baseline to endpoint and responder rate (patients with a reduction of 50% and higher in average pain score compared with baseline). Secondary endpoints were changes in mean NRS pain-related sleep-interference score, overall improvement evaluated by Patient and Clinical Global Impressions of Change (PGIC, CGIC), and impact of the intervention on patient's Health-related quality of life (QOL). All analyses were conducted on an Intention-to-Treat (ITT) analysis data set. RESULTS: At the study endpoint, treatment with melatonin resulted in a considerably higher reduction in the mean NRS pain score in comparison with placebo (4.2 ± 1.83 vs. 2.9 ± 1.56; P-value < 0.001). In terms of treatment responders, a greater proportion of melatonin-treated patients satisfied the responder criterion than placebo-treated patients (63.5% vs. 43.1%). Melatonin also reduced pain-related sleep interference scores more than did placebo (3.38 ± 1.49 vs. 2.25 ± 1.26; P-value < 0.001). Further, at the endpoint, more improvement was also seen in terms of PGIC, CGIC, and Health-related QOL in patients treated with melatonin than placebo. Melatonin was also well tolerated. CONCLUSION: The present results showed that melatonin as an adjunct therapy to pregabalin might be helpful for use in patients with PDN. However, confirmation of these results requires further studies.

Effect of sitagliptin therapy on IL-29 and its associated signaling molecules in patients with type 2 diabetes mellitus.

OBJECTIVE: The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita-), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29, FOS, JUN, NF-AT2, NF-KB1, STAT1-2, IRF1, IRF3, IRF7, and IRF9 was assessed with real-time qPCR. RESULTS: Increased protein and gene levels of IL-29 were observed in Sita- group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita- group (p < 0.001 and p = 0.008). Expression of FOS, NF-AT2 and NF-KB1 in Sita- patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS, NF-AT2, and NF-KB1 was found in Sita+ group versus Sita- parients (p = 0.027, p = 0.003, and p = 0.002). In Sita- patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all). CONCLUSION: Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS, NF-AT2 and NF-KB1 in T2D.

Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.

OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN. METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC. DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects. TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).

Analgesic effect of curcumin topical formulation in knee osteoarthritis patients: a clinical trial.

OBJECTIVES: The aim of this study was to recognize the efficacy and safety of curcumin ointment on patients with knee osteoarthritis (OA) compare to diclofenac as standard medication. METHODS: The topical effects of curcumin (10%) and diclofenac (1%) ointments were assessed through the visual analog scale (VAS) and Western Ontario and McMaster Universities Arthritis (WOMAC) index after three times a day administration for two weeks in 60 patients. RESULTS: Desirable effects compared to the pre-treatment period were observed after two weeks of continuous treatment. Based on our results, VAS and WOMAC index were altered after treatment significantly (p<0.0001). CONCLUSIONS: Two-week use of curcumin ointment could ameliorate the pain, stiffness and function disability in patients with OA.

Increased circulating level of CTRP15 in patients with type 2 diabetes mellitus and its relation with inflammation and insulin resistance.

AIMS: Type 2 diabetes mellitus (T2DM) is a highly prevalence disease that has a close relation with secretory factors such as adipokines and myokines. C1q tumor necrosis factor-α (TNF-α)-related protein 15 (CTRP15) is a paralogue paralogue of adiponectin that has a close relation with insulin resistance and inflammation. The present study aimed to assess circulating levels of CTRP15 in patients with T2DM in comparison with controls and thier association with inflammatory cytokines. METHODS: This case-control study was performed on 80 T2DM patients and 80 controls which diagnosed according to the criteria of American Diabetes Association (ADA). Serum levels of CTRP15, adiponectin, TNF-α, and interleukin- 6 (IL-6) were determined using ELISA kits. RESULTS: The results indicated higher concentration of CTRP15 in T2DM patients (103.17 ± 27.99) compared to the controls (66.11 ± 20.46, p < 0.001), while adiponectin decreased considerably in the patients compared to the controls (p < 0.001). Moreover, circulating levels of IL-6 and TNF-α elevated in the patients compared to the controls (p < 0.001). CTRP15 indicated independent association with BMI and adiponectin in the controls while, in the patients it demonstrated independent association with HOMA-IR and TNF-α. CONCLUSIONS: Higher concentration of CTRP15 in the patients and its relation with insulin resistance and inflammation suggested a relation of CTRP15 with the pathogenesis of diabetes. In addition, it seems likely that patients with T2DM had a CTRP15 resistance; however, future studies are necessary to prove this concept.

Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy.

PURPOSE: Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN. PATIENTS AND METHODS: 113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. RESULTS: Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as ≥50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG. CONCLUSION: The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.