Treatment Of Painful Diabetic Peripheral Neuropathy Research Articles

Conventional management and current guidelines for painful diabetic neuropathy

Painful Diabetic Peripheral Neuropathy (PDN) is common, affecting around a quarter of patients with both type 1 and type 2 diabetes, and can lead to significant curtailment of functionality and quality of life. Patients may present with unremitting burning, aching or “electric-shock” type pains in their feet, legs and later, in the hands. Conventional management approaches must focus not only on pain relief, but also on concurrent sleep problems, mood disorders and functionality. The mainstay of treatment is pharmacotherapy. Most current international guidelines recommend a choice of four drugs: amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for PDN. Recent evidence from the OPTION-DM trial demonstrated that these drugs and their combinations have equivalent efficacy. Moreover, combination treatment provided significant pain relief to patients with inadequate response to the maximum tolerated dose of monotherapy. PDN refractory to pharmacotherapy can be treated with capsaicin 8% or high frequency spinal cord stimulation.

Treatment of Painful Diabetic Neuropathy Using Frequency Rhythmic Electro Magnetic Neural Stimulation (FREMS); Effectiveness in Daily Practice.

Painful diabetic peripheral neuropathy (PDPN) is common and difficult to treat with limited treatment options. We assessed the efficacy of frequency rhythmic electromagnetic neural stimulation (FREMS) in patients with PDPN. An uncontrolled prospective survey of patients with PDPN and pain despite at least two lines of pharmacotherapy. The primary outcome, 50% reduction in pain scores at 1 and/or 3 months post FREMS. FREMS was applied to both legs below the knees using 4 sets of electrodes per leg; the treatment consisted of 10 sessions of 35 min applications given over 14 days. FREMS was repeated every 4 months and patients were followed up for 12 months. Pain was assessed using the neuropathic pain symptom inventory (NPSI) and quality of life (QOL) by the EQ-5D. Out of 336 subjects, 248 patients met the inclusion criteria (56% men), average age and diabetes duration were 65 and 12.6 years respectively. FREMS was associated with a median decrease NPSI of 31% at M1 (range -100;+93%), and a median decrease of -37.5% at M3 (range -100;+250%). The 50% reduction in pain was reached in 80/248 (32.3%) and 87/248 (35.1%) after M1 and M3 respectively. The change in NPSI was accompanied by a decrease in self reported use of opiates of >50%. FREMS treatment was associated with a significant reduction in pain severity over a three months period in patients who did not have adequate response to pharmacotherapy. Randomised (sham)-controlled trials examining the role of FREMS as a treatment for PDPN in non-responders to pharmacotherapy are needed.

455-P: Artificial Intelligence Approach to Treatment Classification in Painful Diabetic Neuropathy

Aim: Our study predicted treatment responses in patients with painful DPN (diabetic peripheral neuropathy) by developing a deep learning model using resting state functional magnetic resonance imaging (fMRI) neuroimaging datasets. Methods: Forty-three consecutive patients who received intravenous lidocaine treatment for painful DPN were assessed. All subjects (responders n=29 and non-responders n=14) underwent detailed clinical and neurophysiological assessments to phenotype their pain sensory profile. Subjects also underwent brain resting-state fMRI. After pre-processing we performed a group concatenated independent component analysis (ICA) set to 30 components and automatically chose 7 highly correlated (p<0.05) ICA components. A 3D convolutional neural network (CNN) classification framework was trained using a VoxNet based architecture. This deep learning architecture compared models using (1) 7 correlated ICA networks 2) all 30 ICA networks generated 3) pre-processed resting state images. Results: The deep learning treatment response classification in a ten-fold cross validation experiment using 7 ICA spatial maps has a mean AUC of 0.85 and an F1-Score of 0.90. However, with the extra information of all 30 ICA maps the mean AUROC increased to 0.97 with an F1-Score of 0.95. Using only pre-processed resting-state fMRI data achieved suboptimal F1-Score of 69% and AUC score of 44%. Conclusion: Through the use of our deep learning model, we have demonstrated high classification performance. Our method improves painful DPN treatment efficiency by stratifying patients to receive the correct treatment from the outset. We believe to our knowledge this is the first study utilising deep learning methods to classify treatment response in painful DPN. Disclosure K.Teh: None. I.D.Wilkinson: None. G.P.Sloan: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None. Funding National Instituteof Health Research Efficacy and Mechanism Evaluation Programme (NIHR 129921) European Foundation for the Study of Diabetes (Microvascular Complications Project Grant) University of Sheffield, Health Education England, Knowledge Exchange

Safety and Efficacy of Pregabalin Treatment and Quality of Life in Patients Treated with Pregabalin in Painful Diabetic Peripheral Neuropathy

The treatment modalities for painful diabetic peripheral neuropathy (PDPN) include antidepressants, anticonvulsants, capsaicin, membrane stabilizers and analgesics. Recent guidelines recommend pregabalin as a first line treatment for PDPN. But controversy exists about its efficacy and safety. The main objective of the study is to determine the safety, efficacy of pregabalin treatment for PDPN. An interventional cohort study was carried out in a tertiary care teaching hospital. Subjects who satisfy the inclusion criteria were included in the study after obtaining written informed consent. A total of 52 subjects were enrolled in the study. PDPN was confirmed by means of (1) Diabetic neuropathy symptom (DNS) score of more than one point, (2) Diabetic neuropathy examination score (DNE) of more than three points, (3) Neuropathic disability score (NDS) of more than 6 points and (4) Pain of more than 50% assessed by Visual Analog Scale (VAS). The subjects received pregabalin 75mg once daily for one week followed by 75 mg twice daily for further 3 weeks based on patient’s tolerability. Pain intensity was measured by using Short-Form McGill pain questionnaire. Safety of therapy was assessed from the incidence of adverse events including physical as well as laboratory evaluations. All study subjects’s enrolled received pregabalin. Study showed that pregabalin treatment significantly reduced pain in diabetic peripheral neuropathy with mean pain score 11.52 ± 9.30 (P value 0.00). The most common adverse effects of pregabalin were dizziness, peripheral edema, and somnolence. The study concluded that pregabalin significantly reduces pain and improve quality of life in PDPN.There was a dose-related increase in efficacy of pregabalin treatment. Moreover, there was a dose-related increase in incidence of most adverse events which are generally mild to moderate. Disclosure C. Radhakrishnan: None. A. Ut: None. S. K: None. N. Manikath: None. R.R. Cr: None.

Searching the optimal composition: combination pharmacotherapy of painful diabetic neuropathy

The review concerns evidence base of combination pharmacotherapy in painful diabetic peripheral neuropathy (DPN). This issue is important to study because current treatments in monotherapy give partial benefit and have dose-limiting and exposure-limiting adverse effects. Combinations of different drug classes with properties of central nociceptive response modulators have been studied, such as anticonvulsants (pregabalin, gabapentin), norepinephrine and serotonin reuptake inhibitors (venlafaxine, duloxetine), tricyclic antidepressants (TCA: amitriptyline, nortriptyline), and also opioids. But the evidence is sufficient only for some combinations, such as TCA with gabapentin, and gabapentin with opioid. Combination of pregabalin and duloxetine has not demonstrated clear benefit in comparison with dose-escalation of monotherapy with pregabalin or duloxetine, although it was non-inferior in terms of efficacy and safety. From the perspective of mechanistic synergy and avoidance of adverse effects addition the combination of the central pain pathway modulators such as ligands of α-2-δ subunit of voltage gated calcium channels with antioxidants and metabolic regulators is promising. High-quality evidence supports the efficacy of pregabalin and alpha-lipoic acid (ALA) as monotherapies in DPN. ALA is inexpensive, widely accessible, and currently the only thoroughly studied nonsedative systemic agent for neuropathic pain. Pregabalin offers the best NNT (average 5,0) in treatment of painful DPN and also improves sleep, mood, and anxiety. Adverse effects profiles are different, thus combining pregabalin with ALA will not affect overall safety and tolerability. The combination of pregabalin with ALA is currently under controlled investigation (ISRCTN14577546).

Clinical efficacy of different doses of lipo-prostaglandin E1 in the treatment of painful diabetic peripheral neuropathy

ObjectiveTo observe the clinical efficacy of different doses of alprostadil (lipo-prostaglandin E1, lipo-PGE1) in the treatment of painful diabetic peripheral neuropathy (DPN). MethodsSixty patients with painful DPN were equally and randomly assigned into three groups. Two groups received different doses of lipo-PGE1 by intravenous drip injection (A group: low-dose lipo-PGE1; B group: high-dose lipo-PGE1) following intravenous bolus injection of mecobalamin (MeCbl, 0.5mg once daily (QD)); the third group received MeCbl alone (C group). All patients received optimized treatment to lower blood glucose, blood pressure, and blood lipids to target levels. The efficacy of lipo-PGE1 in the three groups of patients was observed after 3weeks of treatment. ResultsThe overall response rate was 90% in the B group, significantly higher than that in the A and C groups (80% and 55%, respectively; P<0.05). During the observation period, there was no incidence of serious adverse reactions (e.g., acute heart failure, sudden drop in blood pressure, or malignant arrhythmias) in any of the three groups. ConclusionsHigh-dose lipo-PGE1 has better efficacy than low-dose lipo-PGE1 or MeCbl alone in the treatment of painful DPN.

Pregabalin

Pregabalin

Insensate foot of diabetic foot ulcer can have underlying silent neuropathic pain

Subjects with diabetic foot ulcer (DFU) are believed to be less likely to complain of symptoms of painful diabetic peripheral neuropathy (PDPN). When we assessed this using Leeds Assessment of Neuropathic Symptoms and Signs questionnaire (s-LANSS) we found that out of total 44 subjects with DFU, 19 (43·2%) had possible neuropathic discomfort. s-LANSS score was significantly higher in DFU group (8·1 ± 7·7 versus 4·7 ± 4·6; P = 0·04). However, there was no difference in the perception of pain in 10-point Likert scale (3·9 ± 3·6 versus 3·3 ± 3·0; P = NS) between these two groups. This study suggests that subjects with DFU may suffer from PDPN, but do not perceive it. Further studies are needed to assess if treatment of PDPN in these subjects is beneficial.

Do mood symptoms affect neuropathic pain response to pregabalin?

Anxiety and depression are commonly comorbid with painful diabetic peripheral neuropathy (DPN). Data from 3 randomized, placebo-controlled, 8-13 week trials of pregabalin (300 or 600 mg/d) as treatment of painful DPN were pooled and retrospectively analyzed to investigate relationships between changes in pain and severity of anxiety and depression. Endpoint–LOCF mean pain score (MPS, scale of 0 [no pain] to 10 [worst possible pain]) was the primary efficacy measure, and the Hospital Anxiety and Depression Scale anxiety (HADS-A) and depression (HADS-D) subscales were secondary efficacy measures.