Management Of Painful Diabetic Neuropathy Research Articles

Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Where does spinal cord stimulation fit into the international guidelines for refractory painful diabetic neuropathy? a consensus statement

BackgroundAlthough pharmacotherapy with anticonvulsants and/or antidepressants can be effective for many people with painful diabetic neuropathy (PDN), albeit with frequent side-effects, a critical juncture occurs when neuropathic pain no longer responds to standard first- and second-step mono- and dual therapy and becomes refractory. Subsequent to these pharmacotherapeutic approaches, third-line treatment options for PDN may include opioids (short-term), capsaicin 8% patches, and spinal cord stimulation (SCS). AimThis document summarizes consensus recommendations regarding appropriate treatment for refractory peripheral diabetic neuropathy (PDN), based on outcomes from an expert panel convened on December 10, 2022, as part of the Worldwide Initiative for Diabetes Education Virtual Global Summit, “Advances in the Management of Painful Diabetic Neuropathy.” ParticipantsNine attendees, eminent physicians and academics, comprising six diabetes specialists, two pain specialists, and one health services expert. EvidenceFor individuals with refractory PDN, opioids are a high-risk option that do not provide a long-term solution and should not be used. For appropriately selected individuals, SCS is an effective, safe, and durable treatment option. In particular, high-frequency (HF) SCS (10 kHz) shows strong efficacy and improves quality of life. To ensure treatment success, strict screening criteria should be used to prioritize candidates for SCS. Consensus Process:Each participant voiced their opinion after reviewing available data, and a verbal consensus was reached during the meeting. ConclusionGlobally, the use of opioids should rarely be recommended for refractory, severe PDN. Based on increasing clinical evidence, SCS, especially HF-SCS, should be considered as a treatment for PDN that is not responsive to first- or second-line monotherapy/dual therapy.

Topical capsaicin for the management of painful diabetic neuropathy: a narrative systematic review.

Aim: To investigate the potential benefit of topical capsaicin formulations. Materials& methods: A narrative systematic review was employed. Results: About8% Capsaicin patches were found to significantly reduce symptoms of diabetic peripheral neuropathy. Capsaicin was found to improve sleep quality (p=0.02). Capsaicin patch exposure for 60minshowed significant reduction in symptoms (-32.8%). Capsaicin cream significantly reduced pain at weeks 2 and 6 (p=0.003 andp=0.03, respectively), but not at week 8 in comparative studies. 0.025% Capsaicin gel had an insignificant reduction in pain compared with placebo (p=0.53), however 0.075% was found to be significant (p=0.038). Capsaicin cream did not have superior improvement of pain as compared with clonidine gel (p=0.931). The most common adverse events included application site discomfort, erythemaand burning. Conclusion: Topical capsaicin treatments are a potentially beneficial peripherally acting medication. Further research is needed to determine the best means of ameliorating the side effects of treatments.

Systematic Review and Network Meta-analysis of Neurostimulation for Painful Diabetic Neuropathy.

Different waveforms of spinal cord stimulation (SCS) have now been evaluated for the management of painful diabetic neuropathy (PDN). However, no direct or indirect comparison between SCS waveforms has been performed to date. To conduct a systematic review and network meta-analysis to evaluate the effectiveness of SCS for PDN. MEDLINE, CENTRAL, Embase, and WikiStim were searched from inception until December 2021. Randomized controlled trials (RCTs) of SCS for PDN were included. Pain intensity, proportion of patients achieving at least a 50% reduction in pain intensity, and health-related quality of life (HRQoL) data were extracted. Significant reductions in pain intensity were observed for low-frequency SCS (LF-SCS) (mean difference [MD] -3.13 [95% CI -4.19 to -2.08], moderate certainty) and high-frequency SCS (HF-SCS) (MD -5.20 [95% CI -5.77 to -4.63], moderate certainty) compared with conventional medical management (CMM) alone. There was a significantly greater reduction in pain intensity on HF-SCS compared with LF-SCS (MD -2.07 [95% CI -3.26 to -0.87], moderate certainty). Significant differences were observed for LF-SCS and HF-SCS compared with CMM for the outcomes proportion of patients with at least 50% pain reduction and HRQoL (very low to moderate certainty). No significant differences were observed between LF-SCS and HF-SCS (very low to moderate certainty). Limited number of RCTs and no head-to-head RCTs conducted. Our findings confirm the pain relief and HRQoL benefits of the addition of SCS to CMM for patients with PDN. However, in the absence of head-to-head RCT evidence, the relative benefits of HF-SCS compared with LF-SCS for patients with PDN remain uncertain.

AAN releases updated guideline for management of diabetic neuropathy

New evidence supporting the use of select oral and topical agents for the management of painful diabetic neuropathy is discussed in an updated guideline released in December 2021 by the American Academy of Neurology (AAN).

Distal Symmetric Polyneuropathy Pain in Diabetes Mellitus

Objective: To evaluate neuropathic pain (NP), its intensity, and complications in people with type 2 diabetes mellitus (T2DM) in a city of eastern São Paulo. Method: Cross-sectional study conducted with 96 individuals with T2DM served by primary health units in São João da Boa Vista-SP. The following instruments were used to screen NP: Michigan Neuropathy Screening Instrument, Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique 4, and Brief Pain Inventory. The data were analyzed using descriptive and inferential statistics, with a 5 % significance level. Results: Of the 96 people with T2DM for longer than five years, 22.9 % had pain. NP was related to high levels of fasting blood glucose (mean = 214 ± 65.58 mg/dl; p = 0.0002), glycated hemoglobin (mean = 8.8 ± 0.11 %; p < 0.001), absence of a balanced diet (p = 0.0066), obesity (p = 0.023), and high blood pressure (p < 0.001). Conclusion: Higher values ​​of glycated hemoglobin rates increased three times the chance of NP. The screening and management of painful diabetic neuropathy is a challenge but adopting a screening protocol supports the secondary prevention of this manifestation.

Spinal cord stimulation for the management of painful diabetic neuropathy: a systematic review and meta-analysis of individual patient and aggregate data.

Spinal cord stimulation (SCS) has been suggested as a treatment option for patients with painful diabetic neuropathy (PDN). We conducted a systematic review and undertook a meta-analysis on individual patient data from randomised controlled trials (RCTs) to assess the effectiveness of SCS for the management of PDN. Electronic databases were searched from inception to May 2020 for RCTs of SCS for PDN. Searches identified 2 eligible RCTs (total of 93 patients with PDN) and 2 long-term follow-up studies of one of the RCTs. Individual patient data were obtained from the authors of one of these RCTs. Meta-analysis showed significant and clinically meaningful reductions in pain intensity for SCS compared with best medical therapy alone, pooled mean difference (MD) -3.13 (95% confidence interval [CI]: -4.19 to -2.08) on a 10-point scale at the 6-month follow-up. More patients receiving SCS achieved at least a 50% reduction in pain intensity compared with best medical therapy, pooled risk ratio 0.08 (95% CI: 0.02-0.38). Increases were observed for health-related quality of life assessed as EQ-5D utility score (pooled MD 0.16, 95% CI: 0.02-0.30) and visual analogue scale (pooled MD 11.21, 95% CI: 2.26-20.16). Our findings demonstrate that SCS is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN. Large well-reported RCTs with long-term follow-up are required to confirm these results.

Current Strategies for the Management of Painful Diabetic Neuropathy.

The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.

31-LB: Neuromodulation for Treatment of Painful Diabetic Neuropathy: A Multicenter Randomized Controlled Trial

Background: Six million adults in the U.S. are living with painful diabetic neuropathy (PDN) and current treatments are ineffective for many. Preliminary data suggest 10 kHz spinal cord stimulation (SCS) relieves pain and may improve sensation in refractory patients. Methods: Prospective, multicenter, randomized controlled trial (SENZA-PDN) with 216 subjects assigned 1:1 to 10 kHz SCS (Nevro Corp.) combined with conventional medical management (CMM) or CMM alone. Patients with PDN symptoms ≥12 months, lower limb pain intensity ≥5cm (0-10cm visual analog scale [VAS]), hemoglobin A1c ≤10%, and upper limb pain intensity <3cm were included. Outcomes include pain, neurological function, and quality of life. Results: Randomization of 113 subjects to 10 kHz SCS+CMM and 103 to CMM resulted in groups well-matched at baseline. There were 2 procedure-related infections in the 10 kHz SCS+CMM group (1.8%). At 3-month follow-up, there were clear differences in lower limb pain scores (Fig 1A) and Diabetes Quality of Life (Fig 1B). Patients in the 10 kHz SCS+CMM group demonstrated improvements in sensation on physical examination (Fig 1C) and by patient report of numbness (Fig 1D). In addition, differences between treatment groups were observed in 6-minute walk test distance (Fig 1E) and sleep (Fig 1F). Conclusion: SENZA-PDN is the largest RCT to-date of SCS management of PDN and will inform the treatment continuum. Disclosure E. Petersen: Consultant; Self; Abbott, Medtronic, Neuros Medical, Nevro. Research Support; Self; Medtronic, Neuros Medical, Nevro, ReNeuron. T. Stauss: None. J.L. White: Research Support; Self; Allergan plc., Astellas Pharma Inc., Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Eli Lilly and Company, Fitbit, Inc., Nevro, NovMetaPharma Co. Ltd., Theracos, Inc. S.M. Sills: None. K. Amirdelfan: Consultant; Self; Biotronik, Medtronic, Nevro Corporation, Saluda. M. Guirguis: Consultant; Self; Boston Scientific, nevro incop, spr. J. Xu: None. C. Yu: None. A. Nairizi: None. D.G. Patterson: Research Support; Self; Nevro Corporation. V. Galan: None. N. Mehta: Advisory Panel; Self; Nevro. Research Support; Self; Nevro. S.P. Lad: None. D. DiBenedetto: None. P.W. Wu: None. C.E. Nasr: Other Relationship; Self; Exilxis, Neurogastrx, Nevro Corp. R. Taylor: Consultant; Self; Nevro. E.S. Brooks: Employee; Self; Nevro. J. Subbaroyan: Employee; Self; Nevro Corp. B. Gliner: Employee; Self; Nevro Corp. D.L. Caraway: Employee; Self; Nevro. N. Mekhail: Consultant; Self; Boston Scientific, Nevro, Nuvectra, Relievant, Saluda, Sollis Therapeutics, Vertos Medical. Research Support; Self; Halyard, Mallinckrodt Pharmaceuticals, Mesoblast, Neuros Medical. Funding Nevro Corp.

Pragmatic Opioid Use in Painful Diabetic Neuropathy.

The management of painful diabetic neuropathy poses a tough clinical challenge. Although opioid analgesics are considered as second- or third-line agents in the management of moderate-to-severe neuropathic pain, prescription of opioids for this indication is higher than expected. This narrative review is a recommendation on how to ensure pragmatic use of opioids for those with painful diabetic neuropathy while avoiding complications such as opioid overdose, opioid diversion and the development of opioid-use disorder. Risk mitigation strategies at the level of the clinician include periodic assessment and documentation of clinical details, treatment history and psychosocial status. Using a multimodal approach to pain management, medication counselling, adherence monitoring programmes, evidence-based opioid dosing strategies and empowering patients to make treatment decisions are effective strategies in reducing risk associated with prolonged opioid use. At the organisational and policy level, using prescription drug monitoring programmes, carrying out periodic opioid utilisation reviews and providing training to patients and physicians on safe opioid use are useful, implementable strategies.

Pregabalin in the Management of Painful Diabetic Neuropathy: A Narrative Review.

Pregabalin is a first-line treatment in all major international guidelines on the management of painful diabetic neuropathy (pDPN). Treatment with pregabalin leads to a clinically meaningful improvement in pain scores, offers consistent relief of pain and has an acceptable tolerance level. Despite its efficacy in relieving neuropathic pain, more robust methods and comprehensive studies are required to evaluate its effects in relation to co-morbid anxiety and sleep interference in pDPN. The sustained benefits of modulating pain have prompted further exploration of other potential target sites and the development of alternative GABAergic agents such as mirogabalin. This review evaluates the role of pregabalin in the management of pDPN as well as its potential adverse effects, such as somnolence and dizziness, which can lead to withdrawal in ~ 30% of long-term use. Recent concern about misuse and an increase in deaths linked to its use has led to demands for reclassification of pregabalin as a class C controlled substance in the UK. We believe these demands need to be tempered in relation to the difficulties it would create for repeat prescriptions for the many millions of patients with pDPN for whom pregabalin provides benefit.Plain Language Summary: Plain language summary available for this article.

Mirogabalin and emerging therapies for diabetic neuropathy

There are currently no approved disease-modifying therapies for diabetic neuropathy, and there are only 3 US Food and Drug Administration-approved therapies (pregabalin, duloxetine, and tapentadol) for painful diabetic neuropathy. They each have moderate efficacy with adverse effects limiting optimal dose titration. There is a considerable need for new therapies for the management of painful diabetic neuropathy. We reviewed the potential role of mirogabalin, which like gabapentin and pregabalin modulates the alpha-2/delta-1 subunit of the voltage-gated calcium channel, allowing the influx of calcium and release of neurotransmitters at the synaptic cleft in the central nervous system and spinal cord. It has shown efficacy and good tolerability in a Phase II study in diabetic painful neuropathy and based on the results of two Phase III clinical trials in diabetic painful neuropathy and post-herpetic neuralgia, Daiichi Sankyo submitted a marketing application for neuropathic pain in Japan in February 2018. We have also reviewed potential new therapies, currently in Phase II clinical trials that may modify disease and/or relieve neuropathic pain through novel modes of action.

Long-Term Outcomes in the Management of Painful Diabetic Neuropathy.

Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of ≤3 months' duration. Limited data are available on the long-term outcomes of this chronic disease. The objective of this study was to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 60 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines including the Brief Pain Inventory. At 12-month follow-up, 37.2% (95% confidence interval [CI], 23.0-53.3) of 43 patients with complete data achieved pain reduction of ≥30%, 51.2% (95% CI, 35.5-66.7) achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, Brief Pain Inventory) and 30.2% (95% CI, 17.2-46.1) had achieved both these measures. Symptom management included at least two medication classes in 55.3% and three medication classes in 25.5% (opioids, antidepressants, anticonvulsants). Almost one-third of patients being managed for PDN in a tertiary care setting achieve meaningful improvements in pain and function in the long term. Polypharmacy including analgesic antidepressants and anticonvulsants were the mainstays of effective symptom management.

Duloxetine in Painful Diabetic Neuropathy

To systematically review the evidence for duloxetine in the management of painful diabetic neuropathy (PDN). Electronic searches of Medline and PubMed were performed from 2005 till October 2015 using medical subject headings and free-text words. Two independent reviewers extracted the data and assessed the methodological quality of the selected studies. Twenty-three studies met our inclusion criteria and 8 were considered of high quality and were included to this review. Because of heterogeneity of the studies included in this review, statistical pooling of the data was not possible. We found good evidence for use of duloxetine in PDN over placebo and pregabalin but there was no benefit of duloxetine over amitriptyline. Duloxetine has a beneficial effect over placebo. Nevertheless, the evidence of superiority of duloxetine over pregabalin and amitriptyline should be explored further as there was only 1 trial for each category. Provided majority of the PDN patients share cardiovascular complications, use of duloxetine will be a good option for treating pain associated with PDN over amitriptyline. Future randomized controlled trials should be designed keeping this in mind.

The Need for Improved Management of Painful Diabetic Neuropathy in Primary Care.

The provision of care for patients with type II diabetes in primary care must involve assessing patients for peripheral neuropathy of the feet. Objectives. This paper will demonstrate that painful diabetic neuropathy (PDN) is poorly assessed for and treated in primary care. Methods. A critical analysis of research will be conducted to identify the prevalence and impact of PDN among individuals with type II diabetes. Results. Research evidence and best practice guidelines are widely available in supporting primary care practitioners to better assess for and treat PDN. However, the lack of knowledge, awareness, and implementation of such research and guidelines prevents patients with PDN from receiving appropriate care. Discussion. Much international research exists on the prevalence and impact of PDN in primary care; however, Canadian research is lacking. Furthermore, the quantity and quality of research on treatment modalities for PDN are inadequate. Finally, current research and guidelines on PDN management are inadequately implemented in the clinical setting. Conclusion. The undertreatment of PDN has significant implications on the individual, family, and society. Healthcare practitioners must be more aware of and better implement current research and guidelines into practice to resolve this clinical issue.

Long-term outcomes in the management of painful diabetic neuropathy

Background: Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of duration ≤3 months. Limited data are available on the long-term outcomes of this chronic disease. This study aims to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. Methods: From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 43 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines including Brief Pain Inventory (BPI). Results: At 12-month follow-up, 37.2% of 43 patients achieved pain reduction of ≥30%, 51.2% achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, BPI), and 30.2% (95% CI: 17.2% to 46.1%) had achieved both these measures. Symptom management included at least 2 medication classes in 55.3%, and 3 medications classes (opioids, antidepressants, anticonvulsants) in 25.5%. Conclusions: A sizable minority of patients being managed for PDN in a tertiary care setting achieve meaningful improvement. Polypharmacy, including analgesic antidepressants, anticonvulsants and opioids, is often necessary to attain symptom management.

Tapentadol extended release in the management of peripheral diabetic neuropathic pain.

Tapentadol, a μ-opioid agonist and norepinephrine reuptake inhibitor, has been found to be an effective medication for a wide variety of chronic pain conditions, including back pain, cancer-related pain, and arthritic pain. It has also been found to have fewer gastrointestinal side effects than more traditional opioid-based therapies. More recently, tapentadol extended release has been demonstrated to be effective in the management of painful diabetic neuropathy, an often debilitating condition affecting approximately one-third of all patients with diabetes. This review highlights the most up-to-date basic and clinical studies by focusing on the mechanisms of action of tapentadol and its clinical efficacy, especially with regard to painful diabetic neuropathy.

Biochemical and neurotransmitters changes associated with tramadol in streptozotocin-induced diabetes in rats.

The incidence of diabetes is increasing worldwide. Chronic neuropathic pain occurs in approximately 25% of diabetic patients. Tramadol, an atypical analgesic with a unique dual mechanism of action, is used in the management of painful diabetic neuropathy. It acts on monoamine transporters to inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The purpose of this study was to evaluate the effects of diabetes on the brain neurotransmitter alterations induced by tramadol in rats, and to study the hepatic and renal toxicities of the drug. Eighty Sprague-Dawley rats were divided randomly into two sets: the normal set and the diabetic set. Diabetes was induced in rats. Tramadol was administered orally once daily for 28 days. The levels of DA, NE, and 5-HT in cerebral cortex, thalamus/hypothalamus, midbrain, and brainstem were evaluated in rats. In addition, the renal toxicity and histopathological effects of the drug were assessed. The induction of diabetes altered neurotransmitter levels. Oral administration of tramadol significantly decreased the neurotransmitter levels. Diabetes significantly altered the effects of tramadol in all brain regions. Tramadol affected function and histology of the liver and kidney. The clinical effects of tramadol in diabetic patients should be stressed.

Comparative Efficacy and Safety of Six Antidepressants and Anticonvulsants in Painful Diabetic Neuropathy: A Network Meta-analysis

Background: Anticonvulsants and antidepressants are mostly used in management of painful diabetic neuropathy (PDN). However there are few direct comparisons between drugs of these classes, making evidence-based decision-making in the treatment of painful diabetic neuropathy difficult. Objectives: This study aimed to perform a network meta-analysis and benefit-risk analysis to evaluate the comparative efficacy and safety of these drugs in PDN treatment. Study Design: Comparative effectiveness study. Setting: Medical Education and Research facility in India. Methods: A comprehensive data search was done in PubMed, Cochrane, and Embase up to August 2012. We then systematically reviewed the studies which compared any of 6 drugs for the management of PDN: amitriptyline, duloxetine, gabapentin, pregabalin, valproate, and venlafaxine or any of their combinations. We performed a random-effects network meta-analysis to rank treatments in terms of efficacy and safety. We chose the number of patients experiencing ≥ 50% reduction in pain and number of patient withdrawals due to adverse events (AE) as primary outcomes for efficacy and safety, respectively. We also performed benefit-risk analysis, taking efficacy outcome as benefit and safety outcome as risk. Analysis was intention-to-treat. Results: We included 21 published trials in the analysis. Duloxetine, gabapentin, pregabalin, and venlafaxine were shown to be significantly efficacious compared to placebo with odds ratios (OR) of 2.12, 3.98, 2.78, and 4.43, respectively. Amitriptyline (OR: 7.03, 95% confidence interval [CI]: 1.87, 29.05) and duloxetine (OR: 3.26, 95% CI: 1.04, 9.97) caused more withdrawals than gabapentin. The ranking order of efficacy was gabapentin, venlafaxine, pregabalin, duloxetine/ gabapentin, duloxetine, amitriptyline, and placebo and the ranking order of safety was placebo, gabapentin, pregabalin, venlafaxine, duloxetine/gabapentin combination, duloxetine, and amitriptyline. Benefit-risk balance favored the order: gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin combination, duloxetine, placebo, and amitriptyline. Limitations: We could not include valproate in our analysis owing to the lack of studies reporting the dichotomous efficacy and safety outcomes. Conclusion: Gabapentin was found to be most efficacious and amitriptyline to be least safe among the treatments included in the study. Gabapentin showed most favorable balance between efficacy and safety. Key words: Amitriptyline, diabetic neuropathy, duloxetine, gabapentin, network meta-analysis, pain, pregabalin, valproate, valproic acid, venlafaxine

HIGH PLASMA TNF-α LEVELS AND MONONUCLEAR CELLS iNOS AND TNF-α EXPRESSION AS RISK FACTORS FOR PAINFUL DIABETIC NEUROPATHY

Painful Diabetic Neuropathy (PDN) is one of the most common and annoyingcomplications of diabetes mellitus. The pathogenesis of PDN is complex and still unclear.Recently it has become clear that nitric oxide (NO) and proinflammatory cytokines playan important role in the pathogenesis and maintenance of pain in PDN. Based on thisphenomenon, this study was conducted to investigate whether the cytokine tumornecrosis factor-alpha (TNF-α) and NO, in this case inducible Nitric Oxide Synthase(iNOS), play a role in PDN pathogenesis. The study was carried in two steps. The first step was a cross sectional and the second step was a case-control study. The study was performed in 110 type-2 diabetic patients. The plasma TNF-α levels were determined by ELISA while the expression of TNF-α and iNOS in mononuclear cells were analyzed immunohistochemically. Of 110 subjects, 59 patients suffered from Painful DN (case) and the remaining 51 patients were Painless DN (control). Cross sectionally, plasma TNF-α levels and immunoreactivity for iNOS and TNF-α were higher in patients with more severe pain in the Visual Analog Scale (VAS). There were statistically significant differences (p < 0.05) between mild and severe pain in regard to TNF-α level (15.24 pg/ml ± 5.42 vs. 20.44 pg/ml ± 10.34 ); to iNOS immunoreactivity (9.72 % ± 8.61 vs. 15.6% ± 11.84); and to TNF-α immunoreactivity (13.0 % ± 9. 48 vs. 20.44% ± 11.75). The case control study showed that TNF-α had an odd ratio of 5.053 [CI 95% (2.241-11.392); p < 0.001]. TNF-α immunoreactivity of 4.125 [CI 95% (1.805-9.425); p < 0.001]; and iNOS immunoreactivity of 3.546 [CI 95% (1.613-7.795); p = 0.002]. There were correlations between TNF-α level, TNF-α and iNOS immunoreactivity and VAS with coefficient correlation: 0.330; 0.285 and 0.275 (p < 0.05) respectively. It is concluded that Diabetic Neuropathy patients with high TNF-α levels, iNOS and TNF-α immunoreactivity of mononuclear cells have higher risk for painful DN than painless DN. The higher TNF-α level, iNOS and TNF-α immunoreactivity the more severe was the pain. This supports the hypothesis that TNF-α and iNOS have role in PDN pathogenesis. The results of this research could be applied as a basic for further research in pursuit of better management of PDN