Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Somatosensory network functional connectivity differentiates clinical pain phenotypes in diabetic neuropathy.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether different clinical pain phenotypes of diabetic polyneuropathy (DPN) are distinguished by functional connectivity at rest. METHODS: This was an observational, cohort study of 43 individuals with painful DPN, divided into irritable (IR, n = 10) and non-irritable (NIR, n = 33) nociceptor phenotypes using the German Research Network of Neuropathic Pain quantitative sensory testing protocol. In-situ brain MRI included 3D T1-weighted anatomical and 6 min resting-state functional MRI scans. Subgroup differences in resting-state functional connectivity in brain regions involved with somatic (thalamus, primary somatosensory cortex, motor cortex) and non-somatic (insular and anterior cingulate cortices) pain processing were examined. Multidimensional reduction of MRI datasets was performed using a machine-learning approach to classify individuals into each clinical pain phenotype. RESULTS: Individuals with the IR nociceptor phenotype had significantly greater thalamic-insular cortex (p false discovery rate [FDR] = 0.03) and reduced thalamus-somatosensory cortex functional connectivity (p-FDR = 0.03). We observed a double dissociation such that self-reported neuropathic pain score was more associated with greater thalamus-insular cortex functional connectivity (r = 0.41; p = 0.01) whereas more severe nerve function deficits were more related to lower thalamus-somatosensory cortex functional connectivity (r = -0.35; p = 0.03). Machine-learning group classification performance to identify individuals with the NIR nociceptor phenotype achieved an accuracy of 0.92 (95% CI 0.08) and sensitivity of 90%. CONCLUSIONS/INTERPRETATION: This study demonstrates differences in functional connectivity in nociceptive processing brain regions between IR and NIR phenotypes in painful DPN. We also establish proof of concept for the utility of multimodal MRI as a biomarker for painful DPN by using a machine-learning approach to classify individuals into sensory phenotypes.

Painful and Painless Diabetic Neuropathies: What Is the Difference?

PURPOSE OF REVIEW: The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN. RECENT FINDINGS: Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN. Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.

Increased thalamocortical functional connectivity on discontinuation of treatment in painful diabetic peripheral neuropathy.

Altered functional connectivity has been demonstrated in key brain regions involved in pain processing in painful diabetic peripheral neuropathy (Painful-DPN). However, the impact of neuropathic pain treatment on functional connectivity has not been investigated. Sixteen participants underwent resting state functional MRI (rs-fMRI) when optimally treated for neuropathic pain during their involvement in the OPTION-DM trial and 1-week following withdrawal of treatment. On discontinuation of pain treatment, there was a rise in functional connectivity between the left thalamus and primary somatosensory cortex (S1) and the left thalamus and insular cortex, key brain regions that are involved in cerebral processing of pain. The changes in functional connectivity between scans also correlated with measures of pain (baseline pain severity and neuropathy pain symptom inventory). Moreover, when participants were stratified into higher and lower than average baseline pain sub-groups, the change in thalamic-S1 cortical functional connectivity between scans was significantly greater in those with high baseline pain compared with the lower baseline pain group. This study shows that thalamo-cortical functional connectivity has the potential to act as an objective biomarker for neuropathic pain in diabetes for use in clinical pain trials.

Reduced Thalamic Gamma Aminobutyric Acid (GABA) in Painless but not Painful Diabetic Peripheral Neuropathy.

Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with Painless- and Painful-diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including GABA (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a Magnetic Resonance Spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterised cohort of participants with Painless- and Painful-DPN. Participants with DPN (Painful- and Painless combined) had a significantly lower GABA:H2O ratio compared to those without DPN (Healthy volunteers [HV] and diabetes without DPN [No-DPN]). Participants with Painless-DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and No-DPN, but not Painful-DPN. There was no difference in GABA:H2O in Painful-DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with Painless-DPN may reflect neuroplasticity due to reduced afferent pain impulses. Whereas partially preserved levels of GABA in Painful-DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes.

Higher Sensory Cortical Energy Metabolism in Painful Diabetic Neuropathy: Evidence From a Cerebral Magnetic Resonance Spectroscopy Study.

Alterations in the resting-state functional connectivity and hyperperfusion of pain processing areas of the brain have been demonstrated in painful diabetic peripheral neuropathy (DPN). However, the mechanisms underlying these abnormalities are poorly understood; thus there is good rationale to explore whether there is higher energy consumption in the pain processing areas of the brain. We performed a 31P magnetic resonance spectroscopy study to explore cellular energy usage (bioenergetics) in the primary somatosensory (S1) cortex in a well-characterized cohort of participants with painful and painless DPN. S1 phosphocreatine (PCr):ATP, a measure of energy consumption, was significantly reduced in painful compared with painless DPN. This is indicative of greater S1 cortical energy consumption in painful DPN. Furthermore, S1 PCr:ATP correlated with pain intensity during the MRI. S1 PCr:ATP was also significantly lower in painful-DPN individuals with moderate/severe pain compared with those with low pain. To our knowledge, this is the first study to demonstrate higher S1 cortical energy metabolism in painful compared with painless DPN. Moreover, the relationship between PCr:ATP and neuropathic pain measures shows that S1 bioenergetics is related to the severity of neuropathic pain. S1 cortical energetics may represent a biomarker of painful DPN and could have the potential to serve as a target for therapeutic interventions. ARTICLE HIGHLIGHTS: Energy consumption within the primary somatosensory cortex appears to be greater in painful compared with painless diabetic peripheral neuropathy. The measure of energy metabolism, PCr:ATP, within the somatosensory cortex correlated with pain intensity and was lower in those with moderate/severe compared with low pain. To our knowledge. this is the first study to indicate higher cortical energy metabolism in painful compared with painless diabetic peripheral neuropathy, and thus has the potential to act as a biomarker for clinical pain trials.

Structural Brain Alterations in Key Somatosensory and Nociceptive Regions in Diabetic Peripheral Neuropathy.

OBJECTIVE: Despite increasing evidence demonstrating structural and functional alterations within the central nervous system in diabetic peripheral neuropathy (DPN), the neuroanatomical correlates of painful and painless DPN have yet to be identified. Focusing on structural MRI, the aims of this study were to 1) define the brain morphological alterations in painful and painless DPN and 2) explore the relationships between brain morphology and clinical/neurophysiological assessments. RESEARCH DESIGN AND METHODS: A total of 277 participants with type 1 and 2 diabetes (no DPN [n = 57], painless DPN [n = 77], painful DPN [n = 77]) and 66 healthy volunteers (HVs) were enrolled. All underwent detailed clinical/neurophysiological assessment and brain 3T MRI. Participants with painful DPN were subdivided into the irritable (IR) nociceptor and nonirritable (NIR) nociceptor phenotypes using the German Research Network on Neuropathic Pain protocol. Cortical reconstruction and volumetric segmentation were performed with FreeSurfer software and voxel-based morphometry implemented in FSL. RESULTS: Both participants with painful and painless DPN showed a significant reduction in primary somatosensory and motor cortical thickness compared with HVs (P = 0.02; F[3,275] = 3.36) and participants with no DPN (P = 0.01; F[3,275] = 3.80). Somatomotor cortical thickness correlated with neurophysiological measures of DPN severity. There was also a reduction in ventrobasal thalamic nuclei volume in both painless and painful DPN. Participants with painful DPN with the NIR nociceptor phenotype had reduced primary somatosensory cortical, posterior cingulate cortical, and thalamic volume compared with the IR nociceptor phenotype. CONCLUSIONS: In this largest neuroimaging study in DPN to date, we demonstrated significant structural alterations in key somatomotor/nociceptive brain regions specific to painless DPN and painful DPN, including the IR and NIR nociceptor phenotypes.

The Treatment of Painful Diabetic Neuropathy.

Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.

Preservation of thalamic neuronal function may be a prerequisite for pain perception in diabetic neuropathy: A magnetic resonance spectroscopy study.

Introduction: In this study, we used proton Magnetic Resonance Spectroscopy (1H-MRS) to determine the neuronal function in the thalamus and primary somatosensory (S1) cortex in different subgroups of DPN, including subclinical- and painful-DPN. Method: One-hundred and ten people with type 1 diabetes [20 without DPN (no-DPN); 30 with subclinical-DPN; 30 with painful-DPN; and 30 with painless-DPN] and 20 healthy volunteers, all of whom were right-handed men, were recruited and underwent detailed clinical and neurophysiological assessments. Participants underwent Magnetic Resonance Imaging at 1.5 Tesla with two 1H-MRS spectra obtained from 8 ml cubic volume voxels: one placed within left thalamus to encompass the ventro-posterior lateral sub-nucleus and another within the S1 cortex. Results: In the thalamus, participants with painless-DPN had a significantly lower NAA:Cr ratio [1.55 + 0.22 (mean ± SD)] compared to all other groups [HV (1.80 ± 0.23), no-DPN (1.85 ± 0.20), sub-clinical DPN (1.79 ± 0.23), painful-DPN (1.75 ± 0.19), ANOVA p < 0.001]. There were no significant group differences in S1 cortical neurometabolites. Conclusion: In this largest cerebral MRS study in DPN, thalamic neuronal dysfunction was found in advanced painless-DPN with preservation of function in subclinical- and painful-DPN. Furthermore, there was a preservation of neuronal function within the S1 cortex in all subgroups of DPN. Therefore, there may be a proximo-distal gradient to central nervous system alterations in painless-DPN, with thalamic neuronal dysfunction occurring only in established DPN. Moreover, these results further highlight the manifestation of cerebral alterations between painful- and painless-DPN whereby preservation of thalamic function may be a prerequisite for neuropathic pain in DPN.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy.

Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.

Diabetic Polyneuropathy - Advances in Diagnosis and Intervention Strategies.

Over half of people with diabetes mellitus develop diabetic polyneuropathy (DPN), which is a major cause of reduced quality of life due to disabling neuropathic pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. The latter represents a major health and economic burden, with lower limb amputation rates related to diabetes increasing in the UK. There is a need for early diagnosis of DPN so that early management strategies may be instigated, such as achieving tight glucose control and management of cardiovascular risk factors, in an attempt to slow its progression. To this end, a one-stop microvascular assessment involving a combined eye, foot and renal screening clinic has proven feasible in the UK. Unfortunately, there are currently no approved disease-modifying therapies for DPN. Some disease-modifying agents have demonstrated efficacy, but further large trials using appropriate clinical endpoints are required before these treatments can be routinely recommended. There has been emerging evidence highlighting a reduction in vitamin D levels in cases of painful DPN and the potential for vitamin D supplementation in deficient individuals to improve neuropathic pain; however, this needs to be proved in randomised clinical trials. The use of established agents for neuropathic pain in DPN is limited by poor efficacy and adverse effects, but patient stratification using methods such as pain phenotyping are being tested to determine whether this improves the outcomes of such agents in clinical studies. In addition, innovative approaches such as the topical 8% capsaicin patch, new methods of electrical stimulation and novel therapeutic targets such as NaV1.7 offer promise for the future. This article aims to discuss the challenges of diagnosing and managing DPN and to review current and emerging lifestyle interventions and therapeutic options.

Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs.

There is a high prevalence of painful diabetic polyneuropathy (pDPN) with around one-third of all patients with diabetes suffering from pDPN. pDPN has debilitating consequences, with a major impact on morbidity and quality of life. Unfortunately, there is no globally licenced pharmacotherapy that modulates the underlying disease mechanisms to prevent or halt the progression of diabetic neuropathy. The cornerstone of treatment therefore remains optimising glycaemic control and cardiovascular risk factors, and symptom control. Evidence from placebo-controlled studies has shown that antidepressants and anticonvulsants are effective for alleviating pDPN. Current clinical guidelines recommend the treatment of pDPN through the use of amitriptyline (tricyclic antidepressant), duloxetine (serotonin norepinephrine reuptake inhibitor), gabapentin and pregabalin (α2-δ ligands), tramadol and tapentadol (µ receptor agonists and norepinephrine reuptake inhibitors) and topical agents such as capsaicin (transient receptor potential V1 receptor desensitizer), although the latter is known to cause degeneration of small nerve fibers. pDPN can be difficult to treat, which frustrates healthcare providers, patients and caregivers. There is an additional need for clinical trials of novel therapeutic agents and optimal combinations for the management of pDPN. This article reviews the pharmacological management of pDPN, emerging therapies, the difficulties of placebo response in clinical trials and novel proposed biomarkers of treatment response.

Determinants of Treatment Response in Painful Diabetic Peripheral Neuropathy: A Combined Deep Sensory Phenotyping and Multimodal Brain MRI Study.

Painful diabetic peripheral neuropathy (DPN) is difficult to manage, as treatment response is often varied. The primary aim of this study was to examine differences in pain phenotypes between responders and nonresponders to intravenous lidocaine treatment using quantitative sensory testing. The secondary aim was to explore differences in brain structure and functional connectivity with treatment response. Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. Twenty-nine patients who met the eligibility criteria (responders, n = 14, and nonresponders, n = 15) and 26 healthy control subjects underwent detailed sensory profiling. Subjects also underwent multimodal brain MRI. A greater proportion of patients with the irritable (IR) nociceptor phenotype were responders to intravenous lidocaine treatment compared with nonresponders. The odds ratio of responding to intravenous lidocaine was 8.67 times greater (95% CI 1.4-53.8) for the IR nociceptor phenotype. Responders to intravenous lidocaine also had significantly greater mean primary somatosensory cortex cortical volume and functional connectivity between the insula cortex and the corticolimbic circuitry. This study provides preliminary evidence for a mechanism-based approach for individualizing therapy in patients with painful DPN.

New Perspective in Diabetic Neuropathy: From the Periphery to the Brain, a Call for Early Detection, and Precision Medicine.

Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus. It leads to distressing and expensive clinical sequelae such as foot ulceration, leg amputation, and neuropathic pain (painful-DPN). Unfortunately, DPN is often diagnosed late when irreversible nerve injury has occurred and its first presentation may be with a diabetic foot ulcer. Several novel diagnostic techniques are available which may supplement clinical assessment and aid the early detection of DPN. Moreover, treatments for DPN and painful-DPN are limited. Only tight glucose control in type 1 diabetes has robust evidence in reducing the risk of developing DPN. However, neither glucose control nor pathogenetic treatments are effective in painful-DPN and symptomatic treatments are often inadequate. It has recently been hypothesized that using various patient characteristics it may be possible to stratify individuals and assign them targeted therapies to produce better pain relief. We review the diagnostic techniques which may aid the early detection of DPN in the clinical and research environment, and recent advances in precision medicine techniques for the treatment of painful-DPN.

Prolonged diabetic ketoacidosis associated with canagliflozin.

We report a case of a 63-year-old man who developed diabetic ketoacidosis (DKA) associated with canagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor. He presented acutely unwell with a silent myocardial infarction, diverticulitis and DKA with a minimally raised blood glucose level. Standard therapy for DKA was initiated. Despite this, ketonaemia persisted for a total of 12 days after discontinuation of canagliflozin. Glucosuria lasting for several days despite discontinuation of the medications is a recognised phenomenon. However, this is the longest duration of ketonaemia to be reported. The cause of prolonged SGLT-2 inhibition remains uncertain. Deviation from the normal DKA treatment protocol and use of personalised regimens may be required in order to prevent relapse into ketoacidosis while avoiding hypoglycaemia in those that develop this condition. LEARNING POINTS: Diabetic ketoacidosis (DKA) may develop in the presence of lower-than-expected blood glucose levels in patients treated with a sodium glucose co-transporter 2 (SGLT-2) inhibitor.Certain individuals prescribed with SGLT-2 inhibitors may be more at risk of DKA, for example, those with a low beta cell function reserve, excessive alcohol consumption and a low carbohydrate diet.In order to reduce the risk of SGLT-2 inhibitor-associated DKA, all patients must be carefully selected before prescription of the medication and appropriately educated.Increased serum ketone levels and glucosuria have been reported to persist for several days despite discontinuation of their SGLT-2 inhibitor.Physicians should consider individualised treatment regimens for subjects with prolonged DKA in the presence of SGLT-2 inhibition.

A new look at painful diabetic neuropathy.

The prevalence of diabetes mellitus and its chronic complications continue to increase alarmingly. Consequently, the massive expenditure on diabetic distal symmetrical polyneuropathy (DSPN) and its sequelae, will also likely rise. Up to 50% of patients with diabetes develop DSPN, and about 20% develop neuropathic pain (painful-DSPN). Painful-DSPN can cast a huge burden on sufferers' lives with increased rates of unemployment, mental health disorders and physical co-morbidities. Unfortunately, due to limited understanding of the mechanisms leading to painful-DSPN, current treatments remain inadequate. Recent studies examining the pathophysiology of painful-DSPN have identified maladaptive alterations at the level of both the peripheral and central nervous systems. Additionally, genetic studies have suggested that patients with variants of voltage gated sodium channels may be more at risk of developing neuropathic pain in the presence of a disease trigger such as diabetes. We review the recent advances in genetics, skin biopsy immunohistochemistry and neuro-imaging, which have the potential to further our understanding of the condition, and identify targets for new mechanism based therapies.

A rare cause of metabolic acidosis: ketoacidosis in a non-diabetic lactating woman.

Ketoacidosis occurring during lactation has been described infrequently. The condition is incompletely understood, but it appears to be associated with a combination of increased metabolic demands during lactation, reduction in carbohydrate intake and acute illness. We present a case of a 27-year-old woman, 8 weeks post-partum, who was exclusively breastfeeding her child whilst following a low carbohydrate diet. She developed gastroenteritis and was unable to tolerate an oral diet for several days. She presented with severe metabolic acidosis on admission with a blood 3-hydroxybutyrate of 5.4 mmol/L. She was treated with intravenous dextrose and intravenous sodium bicarbonate, and given dietary advice to increase her carbohydrate intake. She made a rapid and full recovery. We provide a summary of the common causes of ketoacidosis and compare our case with other presentations of lactation ketoacidosis. LEARNING POINTS: Ketoacidosis in the lactating woman is a rare cause of raised anion gap metabolic acidosis.Low carbohydrate intake, starvation, intercurrent illness or a combination of these factors could put breastfeeding women at risk of ketoacidosis.Ketoacidosis in the lactating woman has been shown to resolve rapidly with sufficient carbohydrate intake and intravenous dextrose.Early diagnosis and prompt treatment are essential because the condition is reported to be reversible with a low chance of recurrence with appropriate dietary advice.