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.

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health.

Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world's population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

The effect of vitamin D supplementation on mortality and intensive care unit admission of COVID-19 patients. A systematic review, meta-analysis and meta-regression.

AIMS: The aim of this systematic review and meta-analysis was to investigate the effect of vitamin D supplementation on mortality and admission to intensive care unit (ICU) of COVID-19 patients. METHODS: A systematic search of PubMed, Google Scholar, Embase, Web of Science and medRxiv with terms relative to vitamin D supplementation and COVID-19 was conducted on 26 March 2021. Comprehensive Meta-Analysis software was used for the quantitative assessment of data and random-effects model was applied. To investigate the association between the dose of vitamin D and the outcomes of interest, meta-regression analysis was performed. RESULTS: Two thousand and seventy-eight patients from nine studies with data on mortality were included (583 received vitamin D supplementation, while 1495 did not). Sixty-one (10.46%) individuals in the treated group died, compared to 386 (25.81%) in the non-treated group (odds ratio [OR]: 0.597; 95% CI: 0.318-1.121; p = 0.109). Eight hundred and sixty patients from six studies with data on ICU admission were included (369 received vitamin D supplementation, while 491 did not). Forty-five (12.19%) individuals in the treated group were admitted to ICU, compared to 129 (26.27%) in the non-treated group (OR: 0.326; 95% CI: 0.149-0.712; p = 0.005). No significant linear relationship between vitamin D dose and log OR of mortality or log OR of ICU admission was observed. CONCLUSION: This meta-analysis indicates a beneficial role of vitamin D supplementation on ICU admission, but not on mortality, of COVID-19 patients. Further research is urgently needed to understand the benefit of vitamin D in COVID-19.

High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study.

The worldwide pandemic of 2019 novel coronavirus disease (COVID-19) has posed the most substantial and severe public health issue for several generations, and therapeutic options have not yet been optimised. Vitamin D (in its "parent" form, cholecalciferol) has been proposed in the pharmacological management of COVID-19 by various sources. We aimed to determine whether COVID-19 mortality was affected by serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D status, or cholecalciferol therapy, and to elucidate any other predictors of COVID-19 mortality. Patients hospitalised with COVID-19 were opportunistically recruited from three UK hospitals, and their data were collected retrospectively. Logistic regression was used to determine any relationships between COVID-19 mortality and potential predictors, including 25(OH)D levels and cholecalciferol booster therapy. A total of 986 participants with COVID-19 were studied, of whom 151 (16.0%) received cholecalciferol booster therapy. In the primary cohort of 444 patients, cholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality, following adjustment for potential confounders (ORadj 0.13, 95% CI 0.05-0.35, p < 0.001). This finding was replicated in a validation cohort of 541 patients (ORadj 0.38, 95% CI 0.17-0.84, p = 0.018). In this observational study, treatment with cholecalciferol booster therapy, regardless of baseline serum 25(OH)D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with COVID-19. Further work with large population studies needs to be carried out to determine adequate serum 25(OH)D levels, as well as multi-dose clinical trials of cholecalciferol therapy to assess maximum efficacy.

High-Dose Vitamin D Supplementation Improves Microcirculation and Reduces Inflammation in Diabetic Neuropathy Patients.

We assessed the effect of different doses of vitamin D supplementation on microcirculation, signs and symptoms of peripheral neuropathy and inflammatory markers in patients with type 2 diabetes (T2DM). Sixty-seven patients with T2DM and peripheral neuropathy (34 females) were randomized into two treatment groups: Cholecalciferol 5000 IU and 40,000 IU once/week orally for 24 weeks. Severity of neuropathy (NSS, NDS scores, visual analogue scale), cutaneous microcirculation (MC) parameters and inflammatory markers (ILs, CRP, TNFα) were assessed before and after treatment. Vitamin D deficiency/insufficiency was detected in 78% of the 62 completed subjects. Following treatment with cholecalciferol 40,000 IU/week, a significant decrease in neuropathy severity (NSS, p = 0.001; NDS, p = 0.001; VAS, p = 0.001) and improvement of cutaneous MC were observed (p < 0.05). Also, we found a decrease in IL-6 level (2.5 pg/mL vs. 0.6 pg/mL, p < 0.001) and an increase in IL-10 level (2.5 pg/mL vs. 4.5 pg/mL, p < 0.001) after 24 weeks of vitamin D supplementation in this group. No changes were detected in the cholecalciferol 5000 IU/week group. High-dose cholecalciferol supplementation of 40,000 IU/week for 24 weeks was associated with improvement in clinical manifestation, cutaneous microcirculation and inflammatory markers in patients with T2DM and peripheral neuropathy.

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

Advancements in improving health-related quality of life in patients living with diabetic foot ulcers.

INTRODUCTION: Diabetic foot ulcer (DFU) constitutes a burden to patients with diabetes deteriorating their quality of life. Health related quality of life (HRQoL) can now be quantified with the use of specific tools; some of them provide a holistic approach to patients' well-being, while others are disease specific or even region specific. Many of these tools are applicable to patients with DFU. This review will present current data about the impact different interventions in the management of DFU on quality of life related parameters. AREAS COVERED: We performed a search of literature using keywords 'diabetes mellitus', 'diabetic foot ulcer', 'diabetic foot', 'health related quality of life', 'quality of life' and 'SF-36' to identify studies that contained data about the relationship between different interventions and quality of life of patients with diabetic foot ulcers. EXPERT COMMENTARY: Available data are not sufficient to conclude on the impact of interventions aimed to heal DFU on HRQoL. There is need for more, better designed studies and meta-analysis to estimate the effect of treatments on HRQoL in patients with DFUs. The development of new, diabetic foot specific tools will help to improve our knowledge in this field.

Role of acupuncture in the management of diabetic painful neuropathy (DPN): a pilot RCT.

AIMS: To examine the role of acupuncture in the treatment of diabetic painful neuropathy (DPN) using a single-blind, placebo-controlled RCT and to collect data that would be required in a future definitive study of the efficacy of acupuncture in DPN. METHODS: 45 patients were allocated to receive a 10-week course either of real (53%) or sham (47%) acupuncture. Five standardised acupuncture points on the lower limb of each leg were used in the study: LR3, KI3, SP6, SP10 and ST36. Outcome measures included the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, lower limb pain (Visual Analogue Scale, VAS); Sleep Problem Scale (SPS); Measure Yourself Medical Outcome Profile (MYMOP); 36-item Short Form 36 Health Survey and resting blood pressure (BP). RESULTS: Over the 10-week treatment period, small improvements were seen in VAS -15 (-26 to -3.5), MYMOP -0.89 (-1.4 to -0.3), SPS -2.5 (-4.2 to -0.82) and resting diastolic BP -5.2 (-10.4 to -0.14) in the true acupuncture group. In contrast, there was little change in those receiving sham acupuncture. A moderate treatment effect in favour of active acupuncture was detected in MYMOP scores -0.66 (-0.96 to -0.35) but non-significant effect sizes in LANSS Pain Scale -0.37 (-2.2 to 1.4), resting diastolic BP -0.50 (-3.0 to 1.99) and the SPS -0.51 (-2.2 to 1.16). CONCLUSIONS: We have demonstrated the practicality and feasibility of acupuncture as an additional treatment for people with DPN. The treatment was well tolerated with no appreciable side effects. Larger randomised trials are needed to confirm the clinical and cost-effectiveness of acupuncture in the treatment of DPN. TRIAL REGISTRATION NUMBER: ISRCTN number: 39740785.

Optimal treatment of infected diabetic foot ulcers.

Foot ulceration can lead to devastating consequences in diabetic patients. They are not only associated with increased morbidity but also mortality. Foot infections result as a consequence of foot ulceration, which can occasionally lead to deep tissue infections and osteomyelitis; both of which can result in loss of limb. To prevent amputations prompt diagnosis and treatment is required. Understanding the pathology of the diabetic foot will help in the planning of appropriate investigations and treatment. Clinical diagnosis of infection is based on the presence of discharge from the ulcer, cellulitis, warmth and signs of toxicity; though the latter is uncommon. Deep tissue samples from the ulcer and/or blood cultures should be taken before, but without delaying the start of antibacterial treatment in limb and life-threatening infections. In milder infections wound sampling may direct appropriate antibacterial treatment. Staphylococcus aureus, followed by streptococci are the most common organisms causing infection and antibacterial treatment should be targeted against these organisms in mild infection possibly with monotherapy. But in serious infections combination therapy is required because these are usually caused by multiple organisms including anaerobes. Drug-resistant organisms are becoming more prevalent and methicillin-resistant infections can be treated effectively with a number of oral antibacterials either as monotherapy or in combination. Surgical treatment with debridement, for example, callus removal or drainage of pus form an important part of diabetic foot ulcer management especially in the presence of infection. Occasionally limited surgery including dead infected bone removal may be necessary for resolution of infection. Amputation is sometimes required as a last resort for limb or life preservation.