Painful Diabetic Neuropathy

Mechanical allodynia technique based on the gradual application of Von Frey filaments (Biosep, France) weighing from 0.16 to 26 g on the plantar surface of the hind legs of the animals. The rats were placed in a plexiglass cage and were acclimated for 20 minutes before testing. Painful diabetic neuropathy in rats was mate- rialized by a withdrawal movement or described in terms of the paw. In ascending order of force, each filament was applied to the mid-plantar area of each hind paw five times, with each application being held for 5 s. With- drawal responses to the Von Frey filaments from both hind paws were counted and then expressed as an overall percentage response, i.e. if a rat withdrew 6 times out of a total 10 Von Frey applications, this was recorded as 60% overall response to that Von Frey filament [13].

BDC: Benghazi Diabetes Centre; BMI: Body Mass Index; BPS: British Pain Society; CPS: Canadian Pain Society; DN4: Douleur Neuropathique en 4 questions; EFNS: European Federation of Neurological Sciences (; GBP (£): British Pound Sterling; HbA1c: haemoglobin A1c; IASP: International Association for the Study of Pain; IDF: International Diabetes Federation; LANSS: Leeds assessment of neuropathic symptoms and signs; MENA: Middle East and North Africa; NHS: National Health Service; NICE: National Institute for health and Care Excellence; NPQ: Neuropathic Pain Questionnaire; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; OR: Odd Ratio; OTC: Over The Counter; PCM: paracetamol; PDN: Painful Diabetic Neuropathy; S- LANSS: Self-report Leeds assessment of neuropathic symptoms and signs; SNRIs: Serotonin-Norepinephrine Reuptake Inhibitors; SPSS: Statistical Package for Social Science; StEP: Standardized Evaluation of Pain; TCAs: Tri-Cyclic Anti- depressants; UK: United Kingdom; USA: United States of America; USD ($): United States Dollar

One of the initial questions that must be addressed is what mechanisms trigger Na v 1.8-positive DRG neuron hyperexcit- ability in diabetes. Promising hypotheses include altered gene expression and posttranslational modification of key ion chan- nels (24, 25). For example, methylglyoxal, abundant during hyperglycemia (19, 20), induces posttranslational modifications in Na v 1.8 sodium channels (26) that result in nociceptor hyper- excitability and mechanical allodynia in rodents. In addition, inflammatory mediators, including cytokines and chemokines, may increase Na v 1.8-mediated currents by acutely activating Na v 1.8 ion channels through second-messenger signaling or by enhancing channel expression (27–29). Consistent with this idea, we have shown that chemokines and their receptors are expressed by DRG neurons (30, 31) and that chemokine signaling is important in generating neuropathic pain in experimental mod- els of PDN (30). However, the role of chemokines in generating Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is

Methods: It is a prospective, open labelled, randomized controlled study. A total of 80 patients diagnosed with painful diabetic neuropathy based on Diabetic neuropathy symptom score and Michigan neuropathy screening instrument, were randomized into two groups to receive amitriptyline and pregabalin SR. Amitriptyline was started at 25mg OD and pregabalin SR 75mg OD for 6 weeks with optional dose titration. Patients were assessed for pain relief by using visual analogue scale and an overall improvement in their general condition by patient’s global impression of change scale. Adverse drug reactions were recorded on each follow up.

Painful diabetic neuropathy (PDN) is a significant complication of DM and is thought to be caused, at least in part, by pathological microvascular changes to the small nerve fibres particularly within the feet and hands [5]. These changes lead to a burning pain in a ‘glove and stocking’ distribution that is spontaneous and unpredictable; the pain is not related to physical activity and is often worse at night [6]. PDN is linked with significant impact on physical function and mobility [7] and is associated with negative effect on mood state and quality of life over and above the impact of diabetes alone [8]. PDN affects 16-23% of people with DM [9,10], that is, approximately 600,000 people in the UK.

Abstract: Diabetic peripheral neuropathy (DPN) represents significant burdens to many patients and the public health-care system. Patients with diabetes in rural areas have higher risk of developing complications and having less access to proper treatment. We studied a rural population of patients with diabetes who attended a pharmacist-led free clinic for a diabetic education program. Our objectives were to 1) determine the prevalence of DPN and painful diabetic neuropathy (p-DN) in patients with type 2 diabetes; 2) assess the proportion of patients with DPN and p-DN left undocumented upon physician referral to a pharmacist-led free clinic; and 3) determine the appropriateness of pain medication regimen. We performed a retrospec- tive analysis of clinical records of patients from the Presbyterian College School of Pharmacy (PCSP) Wellness Center located in Clinton, SC. Diagnoses of DPN and/or p-DN were obtained from referral notes in the clinical records and compared with results from foot examinations performed in the free clinic and clinical features. Medication regimens were also obtained and compared using American Academy of Neurology (AAN) treatment guidelines. Within our study population (n=111), the prevalence of DPN was 62.2% (national average of 28%–45%) and that of p-DN was 23.4% (national average of 11%–24%). In p-DN patients (n=26), 53.8% (n=14) had a documented diagnosis of p-DN by the referring physician, and 46.2% (n=12) were identified by the pharmacists. A total of 95% (19 of 20) of the patients treated for p-DN received adequate pharmacological agents, though suboptimal as per clinical guidelines. More than 50% of the patients used subtherapeutic doses of their medications. Gabapentin was the most frequently used medication in our population (65.4%). Patients in rural South Carolina had a higher prevalence of DPN and p-DN with >60% undocumented cases of p-DN. More than 95% of treated patients did not receive optimum therapy according to AAN guidelines. Keywords: polysensory neuropathy, pharmacist-led diabetes clinic, diabetes educator, gaba- pentin, chronic pain free clinic, pain, gabapentin

Considering the large number of pharmacologic therap- ies and the availability of multiple systematic reviews that identified the efficacy trials of these drugs, we decided to follow an ‘umbrella’ [8,9] approach to identify eligible randomized controlled trials (RCTs). In brief, we will identify systematic reviews that compare available therapeutic options for painful diabetic neuropathy to placebo or any other active comparators. Eligible system- atic reviews will be retrieved and used to identify relevant RCTs. We will subsequently build a dataset comprising eligible RCTs to obtain, critically appraise for quality, and extract data from each RCT to be used for the meta-analyses of relevant outcomes. Extracted data will be combined using a network design to draw infer- ences about the absolute and relative efficacy (from dir- ect and indirect comparisons) of individual therapeutic options (Figure 1).

The studies on painful diabetic neuropathy from the SEA region are very limited. A large study from 13 neurology outpatient clinics from Indonesia used the DN4 and Leeds Assessment of Neuropathic Symptoms and Signs score (S- LANSS) in 8160 subjects. 1,779 patients reported neuropathic pain: 9.6% were attributed to diabetic neuropathy, 28.6% to back pain, 19.3% to carpal tunnel syndrome, 10.7% to frozen shoulder syndrome and 6.1% to brachialgia. 47 In a study of 84 patients with diabetes

Abstract: Painful diabetic neuropathy (PDN) is one of the most common complications of dia- betes mellitus. Recently it has become clear that nitric oxide (NO) and proinflammatory cytokines play an important role in the pathogenesis of PDN. We investigated whether the cytokine tumor necrosis factor alpha (TNF-α) and NO play a role in PDN pathogenesis by performing a cross- sectional and a case–control study in 110 type 2 diabetic patients. Of 110 subjects, 59 patients suffered from PDN (cases) and the remaining were painless DN (controls). Cross-sectionally, plasma TNF-α levels and immunoreactivity for inducible NO synthase (iNOS) and TNF-α were higher in patients with more severe pain on the visual analog scale. There were statistically significant differences between mild and severe pain for TNF-α levels, iNOS immunoreactivity, and TNF-α immunoreactivity. There were statistically significant differences between mild and severe pain for TNF-α levels (mean 15.24 pg/mL ± 5.42 vs 20.44 ± 10.34), iNOS immunore- activity (9.76% ± 8.60% vs 15.48% ± 11.56%), and TNF-α immunoreactivity (13.0% ± 9.48% vs 20.44% ± 11.75%). The case–control study showed that TNF-α had an odds ratio of 5.053 (P , 0.001), TNF-α immunoreactivity of 4.125 (P , 0.001), and iNOS immunoreactivity of 3.546 (P = 0.002). DN patients with high TNF-α levels, and high iNOS and TNF-α expression in macrophages are at risk of suffering from pain. The higher the TNF-α level, and iNOS and TNF-α immunoreactivity, the more severe the pain. These findings could form the basis of further research into better management of PDN.

Results: We identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.

thy should be considered annually. Phys- ical exam may reveal a decrease in pres- sure or vibratory sensation or altered superficial pain and temperature sensa- tion. A simple vibratory sensation exam consists of a tuning fork placed on the bony prominence at the dorsum of the great toe. Patients should be asked to state when they first feel the vibration and when it ceases. This should be repeated twice on each foot. Pressure sensation is gauged with a 10-g monofil- ament. The monofilament is placed at a Painful diabetic neuropathy is a com-

CONSORT2010: Consolidated standards for reporting of trials statement 2010; DD: Dense-disperse; DKMs: Doctors of Korean medicine; DM: Diabetes mellitus; DPN: Diabetic peripheral neuropathy; FDA: Food and Drug Administration; HbA1c: Hemoglobin A1c; HF: High frequency stimulation; HRQoL: Health-related quality of life; ITT: Intention-to-treat; IRB: Institutional review board; LF: Low frequency stimulation; MMRM: Mixed model for repeated measures; MNSI: Michigan neuropathy screening instrument; PDN: Painful diabetic neuropathy; PGIC: Patient global impression of change; PI-NRS: 11-point pain intensity numerical rating scale; PP: Per-protocol; PPI: Present pain intensity; RCTs: Randomized clinical trials; SF-36: Short-form 36v2 health survey; SF-MPQ: Short-form McGill pain questionnaire; SOPs: Standard operating procedures; STRICTA2010: Standards for reporting interventions controlled trials of acupuncture 2010; TENS: Transcutaneous electrical nerve stimulation; VAS: Visual analogue scale.

Despite the novelty of the fi ndings, several limitations warn against the overgeneralization of the results. The fi rst limitation of this study is the relatively small number of subjects. More studies with larger sample sizes are war- ranted. A second limitation of the present study is the relatively short duration of the intervention. Similar stu- dies are needed with longer follow-up duration to validate our fi ndings. Third, due to structural constraints, the num- ber of studied biomarkers was limited, and serum levels of other OTS and in fl ammatory biomarkers were not assessed. Further, only two samples were taken from each patient at baseline and 8 weeks after treatment. Therefore, the quality of the data does not allow a deeper inspection and understanding of the biochemical changes of diabetic neuropathy. Fourth, the statistical data analysis was performed per protocol, while an intent-to-treat ana- lysis might have allowed observation of a modi fi ed pattern of results. Last but not least, we used a relatively modest dose of NAC in our study and we kept the NAC dosage stable throughout the entire study, perhaps higher doses of NAC would have allowed an even more favorable pattern of results.

study, CBZ significantly improved the QoL score in diabetic patients with PDN. Moreover, the patients were able to work/ volunteer for at least 6 hours daily and also had energy to make plans for one evening of social activity during the week and were active over the weekends. The safety profile of CBZ in this study was consistent with earlier studies. 14,25

Our study is the first to provide initial data related to the point prevalence of painful diabetic neuropathy in Libya. We found that 41.3% of parti- cipants, in this small sample, diagnosed with dia- betes that has persisted for at least five years presented with painful diabetic neuropathy. This estimate is of similar magnitude to previous reports on larger samples from populations in the Middle East. For example, Jambart et al. [22] estimated the point prevalence of painful diabetic neuropathy to be 53.7% in a population of 4097 from five different MENA countries. However, our estimate is prelimin- ary and based on a study designed to translate the LANSS into Arabic. The small sample size of partici- pants recruited from a single clinic from one city means that the estimate should be treated with caution. A large multi-site epidemiological study is needed. Our study found that plasma glucose levels were higher than normal ranges for patients with diabetes, especially in patients with possible painful diabetic neuropathy. This might support the theory that painful diabetic neuropathy is more common in patients with poorly controlled diabetes [23]. Our finding that none of the female participants reported being smokers is consistent with data from the Tobacco Atlas that only 0.9% of females aged >15 years in Libya are daily smokers [24].

Abstract: Diabetic peripheral neuropathy is a common complication of diabetes. It presents as a variety of syndromes for which there is no universally accepted unique classification. Sensorimotor polyneuropathy is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community. Pain is the reason for 40% of patient visits in a primary care setting, and about 20% of these have had pain for greater than 6 months. Chronic pain may be nociceptive, which occurs as a result of disease or damage to tissue with no abnormality in the nervous system. In contrast, neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Persistent neuropathic pain interferes significantly with quality of life, impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with depression, anxiety, and noncompliance with treatment. Painful diabetic peripheral neuropathy is a difficult-to-manage clinical problem, and patients with this condition are more apt to seek medical attention than those with other types of diabetic neuropathy. Early recognition of psychological problems is critical to the management of pain, and physicians need to go beyond the management of pain per se if they are to achieve success. This evidence-based review of the assessment of the patient with pain in diabetes addresses the state-of-the-art management of pain, recogniz- ing all the conditions that produce pain in diabetes and the evidence in support of a variety of treatments currently available. A search of the full Medline database for the last 10 years was conducted in August 2012 using the terms painful diabetic peripheral neuropathy, painful diabetic peripheral polyneuropathy, painful diabetic neuropathy and pain in diabetes. In addition, recent reviews addressing this issue were adopted as necessary. In particular, reports from the American Academy of Neurology and the Toronto Consensus Panel on Diabetic Neuropathy were included. Unfortunately, the results of evidence-based studies do not necessarily take into account the presence of comorbidities, the cost of treatment, or the role of third-party payers in decision-making. Thus, this review attempts to give a more balanced view of the management of pain in the diabetic patient with neuropathy and in particular the role of pregabalin. Keywords: diabetes mellitus, painful neuropathy, pain, treatment, pregabalin

http://www.nature.com/nrneurol/journal/v3/n6/full/ncpn euro0504.html [Last accessed on 2011 Oct 31]. Hovaguimian A, Gibbons CH. Clinical approach to the treatment of painful diabetic neuropathy. Ther Adv Endocrinol Metab 2011;2:27-38. [PUBMED] Baig H, Singh K, Sharma A, Obera P, Kaushik S, Nayak D, et al. Role of Cephlandra indica Ø in the management of Diabetes mellitus as an add on medicine along with conventional anti-diabetics. Clinical Research Studies Series II. Central Council for Research in Homoeopathy, New Delhi; 2009:15- 20.

The pain associated with diabetic peripheral neuropathy may be in part due to failure of the endogenous analgesic mechanisms in the descending spinal pathways that control pain transmission to the brain (Tanenberg et al., 2011). The patients with PDN (Painful Diabetic Neuropathy) experience reduced mobility, fatigue, limitations in social activity, diabetic foot infections, sleep impairment, anxiety, and depression (Schmader, 2002; Gore et al., 2005). A study have reported that increased age, increased duration of diabetes, and poor glycaemic control increases the risk of PDN (Franklin et al., 1994). According to the International Association for the Study of Pain, DPN is defined as "pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes." DPN is described as a burning, tingling, prickling, aching, sharp pain characterized by symptoms that are symmetric and distal, often worsening at night and sometimes associated with allodynia, hyperalgesia, and paresthesia (Boyle et al., 2012). Peripheral neuropathies manifest with painful or painless symptoms and many patients experience both.

Unfortunately, treatment algorithms for painful diabetic neuropathy are based upon clinical experience and pooled data from trials with relatively small sample sizes, nonstan- dardized markers of efficacy, and short follow-up studies. Furthermore, there is a lack of data from head-to-head comparison trials, which prohibits true evaluation of the safety and efficacy of widely used neuropathic pain agents. Trials are needed that use 1) head-to-head comparisons or individual neuropathic pain medication or combinations of pain medications, 2) longer durations of follow-up, and 3) use of standardized and validated pain assessment scales to allow accurate comparison of data across trials. 32

While in painful diabetic neuropathy anodal tDCS produces pain relief, in chronic lower back pain and postoperative pain the results were conflicting, while cathodal nor anodal tDCS was [r]