中国南方汉族人群中卡马西平导致SJS/TEN与HLA-B基因的相关性

目的:探讨中国南方汉族人群中卡马西平(CBZ)所致Stevens-Johnson综合征/中毒性表皮坏死松解症(SJS/TEN)与HLA-B基因的相关性。方法:采用病例对照研究,收集11例CBZ-SJS/TEN患者(CBZ-SJS/TEN组)、93例CBZ耐受患者(CBZ耐受组)及93例未服用抗癫痫药物的正常人(正常对照组)。PCR和测序法检测其HLA-B*1502基因型;χ2检验分析HLA-B*1502及其他HLA-B位点与CBZ-SJS/TEN的相关性。结果:CBZ-SJS/TEN组的HLA-B*1502基因阳性率为72.7%,显著高于CBZ耐受组及正常对照组。3例HLA-B*1502阴性CBZ-SJS/TEN患者的基因型分别为HLA-B*1511/1511、5401/5401及4001/4601。除HLA-B*1502之外,HLA-B*1511基因频率在CBZ-SJS/TEN患者与中国南方汉族正常人群之间具有显著的统计学差异,其他位点差异均无显著性。结论:在我国南方汉族人群中HLA-B*1502与CBZ-SJS/TEN具有相关性,建议汉族人群在服用CBZ前应该进行基因型检测。同时,对HLA-B*1502阴性个体使用CBZ治疗时,需密切监视,避免SJS/TEN的出现。     

Assessing neuropathic pain in patients with low back‐related leg pain: Comparing the painDETECT Questionnaire with the 2016 NeuPSIG grading system

Background

Low back‐related leg pain with nerve root involvement is conceptually regarded as a neuropathic condition. However, it is uncertain to what extent patients with this condition can be formally classified with neuropathic pain.

Method

First, we used the 2016 revision of the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) grading system for neuropathic pain to grade patients suffering from low back‐related leg pain and a corresponding disc herniation with either unlikely, possible, probable or definite neuropathic pain. Examination included bedside quantitative sensory testing. Next, we used the clinical classification based on the 2016 NeuPSIG grading system as a reference standard to assess the ability of the painDETECT Questionnaire to identify patients with neuropathic pain.

Results

Of the 50 included patients, six (12%) fulfilled the clinical classification criteria for probable and 44 (88%) for definite neuropathic pain, while none were graded unlikely or possible. According to painDETECT, 23 patients (46%) were classified with unlikely neuropathic pain, 18 patients (36%) had an uncertain condition and in nine patients (18%) neuropathic pain was likely. Among the 44 patients graded as having definite neuropathic pain by the clinical classification, eight were classified as likely neuropathic pain by painDETECT, resulting in an agreement of 18%. Of these 44 patients graded with definite neuropathic pain, painDETECT classified 21 patients (48%) as unlikely and 15 (34%) as uncertain.

Conclusion

Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in patients with low back‐related leg pain.

Significance

The painDETECT Questionnaire performed poorly at detecting neuropathic pain among patients with low back‐related leg pain, compared to clinical examination based on the 2016 NeuPSIG grading system as a reference standard. Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in this population.     

Impact of polymorphisms of the major histocompatibility complex class II,interleukin‐10, tumor necrosis factor‐α and cytotoxic T‐lymphocyte antigen‐4 genes on inhibitor development in severe hemophilia A

Summary. Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case‐controlled cohort study, 260 severely affected, mutation‐type‐matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin‐10 (IL‐10), tumor necrosis factor‐α (TNF‐α) and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF‐α, the A allele of the ?308G>A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL‐10, the ?1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high‐TNF‐α/high‐IL‐10 producers, as compared with 3% of non‐inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA‐4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the ?308G>A polymorphism in TNF‐α and ?1082A>G in IL‐10 in inhibitor patients confirmed the earlier published data. The CT60 single‐nucleotide polymorphism in CTLA‐4 is of apparently less importance.     

HLA‐B27 testing: A journey from flow cytometry to molecular subtyping

Background

Determination of HLA‐B27 status plays an important role as adjuvant in suspected cases for diagnosis of Ankylosing Spondilytis (AS). Objectives of this study were to evaluate (i) flow cytometry method in comparison with DNA microarray for HLA‐B27 typing and (ii) EUROArray HLA‐B27 Direct assay for HLA‐B27 allele detection along with discrimination of AS/non‐AS subtypes in Indian population.

Methods

A total of 7543 patients with a presumptive clinical diagnosis of AS were referred for screening of HLA‐B27. All samples were initially tested by flow cytometry, and based on its findings, 1560 samples were analyzed for the presence of HLA‐B27 allele by microarray technology. A subset of samples (n = 200) were further tested by DNA sequencing for identification of HLA‐B27 subtypes.

Results

Screening of HLA‐B27 by flow cytometry reported 1551 positive (20.56%) and 5556 negative (73.65%) cases. Remaining 436 (5.78%) samples were identified within equivocal zone. Of cases (n = 1560) analyzed by microarray method, 1333 (85.44%) and 227 (14.55%) were detected microarray positive and negative, respectively. DNA sequencing identified HLA‐B*27:07 as the predominant subtype among cases showing ex2 positivity by microarray method. Of 200 cases, 20 cases (14 of HLA‐B*07 and 6 of HLA‐B*37) of HLA‐B27 cross‐reactive subtypes were also identified.

Conclusion

We recommend DNA typing as a complementary tool along with flow cytometry to accomplish successful HLA‐B27 phenotype determination. This is the first study among Indian population to evaluate efficacy of EUROArray to detect B27 allele and its potential to indicate the presence of nondisease‐associated alleles in Indian population.

     

A prospective,open‐label,multicentre study of pregabalin in the treatment of neuropathic pain in Latin America

Aims: The objective of this study was to evaluate the safety and efficacy of pregabalin at flexible doses of 150–600 mg/day in Latin American patients with neuropathic pain. Methods: A prospective, multicentre, open‐label, non‐comparative study included patients age ≥ 18 years diagnosed with neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy‐induced peripheral neuropathic pain (PNP), or human immunodeficiency virus‐related PNP. Eligible patients (N = 121) had a score of ≥ 40 mm on the visual analogue scale and a daily pain rating scale (DPRS) score of ≥ 4 throughout screening. Patients received flexible‐dose pregabalin (150–600 mg/day) for 12 weeks, which included a 4‐week dose‐adjustment phase. The primary efficacy measure was change from baseline to end of treatment/last observation carried forward (EOT/LOCF) in weekly mean pain score on the DPRS. Secondary efficacy measures included pain, anxiety, sleep interference, treatment satisfaction and Patient and Clinician Global Impression of Change. Results: Pregabalin significantly reduced the weekly mean pain score on DPRS from baseline to EOT/LOCF [–3.8 (95% CI: ?4.2 to ?3.3); p < 0.0001]. Reductions from baseline to EOT/LOCF were observed for all secondary efficacy outcomes (p < 0.0001). Pain and sleep interference were significantly improved compared with baseline across all weeks of the study, as early as 1 week after initiation of pregabalin (p < 0.0001). The most common adverse events (AEs) were somnolence, dizziness, weight gain and peripheral oedema. Nine (7.4%) patients discontinued the study because of AEs and 25 (20.7%) temporarily stopped or reduced their pregabalin dose because of AEs. Conclusions: Flexible‐dose pregabalin (150–600 mg/day) significantly reduced pain and anxiety and improved sleep and was generally well tolerated in Latin American patients with neuropathic pain.     

Carbamazepine-induced cutaneous reactions: A simple assay to identify patients carrying the HLA-A*31:01 allele

Abstract

Aims. Treatment with the first-line antiepileptic drug, carbamazepine (CBZ), is associated with adverse cutaneous reactions in up to 10% of patients. One predisposition to these side-effects has been linked to the HLA-A*31:01 allele. HLA-typing is costly and time-consuming. A single nucleotide polymorphism (SNP, rs1061235A > T) has been suggested as a marker for the HLA-A*31:01 allele. We sought to develop and validate a simple, fast and inexpensive assay for rs1061235 to apply in the Norwegian population. Methods. We designed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for the SNP and tested it on a set of 16 samples with known HLA-A alleles. Results. The assay identified all HLA-A*31:01 alleles present, but also marked for HLA-A*33:03. In a second set of 204 samples from Norwegian epilepsy patients with unknown HLA alleles, nine samples heterozygous for the rs1061235 were found. Subsequent HLA-typing showed that one sample was HLA-A*33:01, whereas the other eight were identified as HLA-A*31:01. The remaining 195 samples were correctly identified as neither carrying the rs1061235 SNP nor HLA-A*31:01. The sensitivity and specificity of the rs1061235 SNP test was 100% and 99.5%, respectively. Misinterpretation of the rare HLA-A*33 variants as HLA-A*31:01 has minor consequence, as it only would result in choosing an alternative drug to CBZ. Conclusion. We have designed and validated a simple, fast and inexpensive test for the rs1061235A> T SNP as a marker for HLA-A*31:01 in the Norwegian population for potential use in a personalized treatment approach to patients planned to receive CBZ.     

Pregabalin Vs. Opioids for the Treatment of Neuropathic Cancer Pain: A Prospective,Head‐to‐Head,Randomized, Open‐Label Study

Objectives

Neuropathic cancer pain (NCP) is a common manifestation of cancer and/or its treatment. Treatment following the WHO analgesic ladder provides relief for the majority of cancer pain patients; however, concern remains that opioids may be less efficacious for neuropathic pain (NP) compared with nociceptive pain, often necessitating the use of higher doses. Adjuvants, such as pregabalin, have shown to be efficacious for the treatment of NP, although data come mostly from noncancer studies. The comparative efficacy and safety of opioids versus adjuvants has not been studied for NCP. The aim of this study was to directly compare pregabalin versus a strong opioid for the treatment of NCP.

Methods

A total of 120 patients, diagnosed with “definite” NCP, were randomized into two groups and received increasing doses of either oral pregabalin or transdermal fentanyl for 28 days. VAS score, patient satisfaction, need for opioid rescue, and adverse events (AEs) were recorded.

Results

In the pregabalin group, a significantly higher proportion of patients achieved at least 30% reduction in VAS compared with the fentanyl group (73.3%, 95% CI: 60.3%–83.93 vs. 36.7%, 95% CI: 24.5%–50.1%, P < 0.0001, respectively), while the percentage mean change from baseline was also significantly different [46% (95% CI: 39.5%–52.8%) for pregabalin and 22% (95% CI: 14.9%–29.5%) for fentanyl (P < 0.0001)]. Patient‐reported satisfaction was more frequent with pregabalin, while AEs and treatment discontinuations were more frequent in the fentanyl group.

Discussion

Prompt use of a neuropathic pain‐specific adjuvant, such as pregabalin, in NCP may lead to better control of the neuropathic component, with opioid‐sparing effects.     

Population pharmacokinetic—pharmacodynamic modeling of ketamine‐induced pain relief of chronic pain

Aims: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic—pharmacodynamic (PK—PD) modeling study on the effect of S(+)‐ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS‐1) patients. Methods: Sixty CRPS‐1 patients were randomly allocated to received a 100‐h infusion of S(+)‐ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK—PD model was developed to analyze the S(+)‐ketamine‐pain data. Results: Plasma concentrations of S(+)‐ketamine and its metabolite decreased rapidly upon the termination of S(+)‐ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK—PD model with parameters C₅₀=10.5±4.8 ng/ml (95% ci 4.37–21.2 ng/ml) and t½ for onset/offset=10.9±4.0 days (5.3–20.5 days). Discussion: Long‐term S(+)‐ketamine treatment is effective in causing pain relief in CRPS‐1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present.     

Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: A randomized,double‐blind study

Seven published, randomized, placebo‐controlled clinical trials with pregabalin have shown robust efficacy for relief of neuropathic pain from DPN and PHN. An investigation of the efficacy and safety of twice daily pregabalin enrolled 395 adults with painful DPN for ≥1 year in a 12‐week, double‐blind, placebo‐controlled trial. Patients were randomized to placebo, 150, 300, or 600mg/day pregabalin (n=96, 99, 99, and 101). Primary efficacy measure was change from baseline in endpoint mean pain score from patients’ daily pain diaries. Secondary efficacy measures included pain‐related sleep‐interference scores, Patient and Clinical Global Impressions of Change (PGIC, CGIC), and the EuroQOL Health Utilities Index (EQ‐5D). Statistically significant reduction in pain was observed in patients receiving pregabalin 600mg/day, and 46% of patients treated with 600mg/day pregabalin reported ≥50% improvement in mean pain scores from baseline (vs 30% of placebo patients, p=0.036). Number needed to treat to achieve such response was 6.3. Pregabalin 600mg/day was significantly superior to placebo in improving pain‐related sleep‐interference scores (p=0.003), PGIC (p=0.021), and CGIC (p=0.009). (Neither pregabalin 150 nor 300mg/day separated from placebo on these measures, largely because of an atypically large placebo response in one country representing 42% of patients.) All pregabalin dosages were superior to placebo in improving EQ‐5D utility scores (all p≥0.0263 vs placebo). Pregabalin was well tolerated at all dosages; adverse events were generally mild to moderate. Number needed to harm (discontinuation because of adverse events) was 10.3 for pregabalin 600mg/day.     

Socio‐demographic and clinical profile of chronic pain with neuropathic characteristics in sub‐Saharan African elderly

Data on characteristics of neuropathic pain (NP) in sub‐Saharan Africa are scarce, especially in the elderly. We conducted this study to appreciate the socio‐demographic and clinical profile of chronic pain (CP) with neuropathic characteristics in sub‐Saharan African elderly with musculoskeletal pain. From January to December 2011, we performed a cross‐sectional study in all Rheumatology outpatients over 60 years at the Center for Gerontology and Geriatrics, Dakar, Senegal. In this study, we included patients who experienced musculoskeletal pain for 3 months or longer (CP) and with a DN4 score ≥ 4 (NP). A complete clinical examination was performed to make the diagnosis of NP ‘definite’ or ‘probable’, and to identify the aetiologies of NP. During the study period, 698 outpatients were examined. There were 394 out of the 549 patients over 60 years who reported CP. Among them, 28 patients (7.1%) scored ≥4 on the DN4 questionnaire. Female patients, low educational attainment, manual professions, non‐workers and diabetes were associated with NP (p < 0.05). The symptoms described by patients with NP, often intricate, were lumboradiculalgia (n = 9), cervico‐brachial neuralgia (n = 3), polyneuropathy (n = 12) and mononeuropathy (n = 6). The presumed aetiologies in patients with NP were: chronic spine diseases (n = 14), painful diabetic peripheral neuropathy (n = 8), Sjögren's syndrome (n = 1), tarsal tunnel syndrome in rheumatoid arthritis (n = 1) and bone metastasis (n = 1). No aetiology was identified among three patients. Chronic spine diseases associated with radiculopathies and diabetic neuropathy are the main causes of NP, well detected by DN4 questionnaire and clinical examination in Senegalese sub‐Saharan African elderly.     

Endoneurial pathology of the needlestick‐nerve‐injury model of Complex Regional Pain Syndrome,including rats with and without pain behaviors

Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick‐nerve‐injury (NNI) to one tibial nerve of outbred Sprague–Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post‐traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain‐behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham‐operated controls were removed 14 days post‐surgery for morphometric analysis. PGP9.5⁺ unmyelinated‐fibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood‐vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non‐hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial blood‐vessels. Similar pathological changes have been identified in CRPS‐I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralateral nerves might potentially contribute to extraterritorial pain in CRPS.     

Modulation of sensitized C‐fibers by adrenergic stimulation in human neuropathic pain

The chronic constriction injury model is widely used in studying mechanisms of neuropathic pain. In this model neuropathic pain can be influenced by sympathetic interventions. It is assumed that similar mechanisms as in animals are responsible for pain arising from nerve entrapment syndromes in humans. The aim of the present study was to investigate if in patients with nerve entrapment nociceptive afferents can be modulated by adrenergic stimulation. Methods: Twenty patients with pain due to a unilateral entrapment of the median nerve and 10 controls were included in the study. Spontaneous pain, mechanical and thermal evoked pain were assessed within the innervation territory of the lesioned nerve and the corresponding contralateral segment in patients and on the right hand side in healthy volunteers. The examinations were performed at baseline, during whole body cooling (sympathetic activation) and whole body warming (sympathetic inhibition), and after norepinephrine iontophoresis. Results: All patients reported spontaneous pain. Mechanical allodynia, punctate hyperalgesia and cold allodynia was not found. According to side‐to‐side differences in heat pain thresholds, patients were separated in patients with (n=10) and without (n=10) heat hyperalgesia. Adrenergic stimulation did not induce or enhance spontaneous or mechanical evoked pain in any patient or control subject. However in patients with pre‐existing heat hyperalgesia sympathetic stimulation aggravated heat hyperalgesia significantly. Further in these patients the decrease in heat pain thresholds observed after norepinephrine iontophoresis was significantly higher compared to patients without pre‐existing heat hyperalgesia. Conclusion: Sympathetic–afferent interaction does not play a major role in pain generation due to nerve entrapment. Nevertheless in a subgroup of patients nociceptive afferents show sensitivity to physiological and pharmacological sympathetic stimulation. This finding is important because it emphasises that despite there is no clinical detectable effect on pain sympathetic afferent interaction can be found.     

Intrathecal Ziconotide for Neuropathic Pain: A Review

Neuropathic pain is a considerable burden that affects activities of daily living. The management of neuropathic pain can be challenging because of multiple etiologies and complex manifestations. Ziconotide is a nonopioid intrathecal (IT) analgesic option for patients with neuropathic pain refractory to conventional treatments. The objective of this article is to review the published literature on ziconotide for the treatment of neuropathic pain. Relevant publications were identified through searches of all years of 6 databases, which included PubMed, EMBASE, and CINAHL. Search terms used were ziconotide, SNX‐111, MVIIA, Prialt, and neuropathic pain. Publications were included if ziconotide was intrathecally administered (either alone or in combination with other IT agents) to treat neuropathic pain of any etiology and if pain assessment was an outcome measure. Data extracted included study design, IT drug doses, pain outcome measures, and adverse events (AEs). Twenty‐eight articles met the inclusion criteria: 5 were preclinical studies and 23 were clinical studies. In the preclinical studies, ziconotide demonstrated antiallodynic effects on neuropathic pain. Data from double‐blind, placebo‐controlled (DBPC) trials indicated that patients with neuropathic pain reported a mean percent improvement in pain score with ziconotide monotherapy that ranged from 15.7% to 31.6%. A low starting dose and slow titration of ziconotide resulted in an improved safety profile in the aforementioned trials. Common AEs associated with ziconotide include nausea and/or vomiting, dizziness, confusion, urinary retention, and somnolence. Evidence from DBPC trials, open‐label studies, case series, and case studies suggests that ziconotide, as either monotherapy or in combination with other IT drugs, is a potential therapeutic option for patients with refractory neuropathic pain. Additional studies are needed to establish the long‐term efficacy and safety of ziconotide for neuropathic pain.     

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures

Introduction

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most severe dermatologic conditions occurring in the inpatient setting. There is a lack of consensus regarding appropriate management of SJS and TEN.

Purpose

The scientific literature pertaining to SJS and TEN (subsequently referred to as SJS/TEN) is summarized and assessed. In addition, an interventional approach for the clinician is provided.

Methods

PubMed was searched with the key words: corticosteroids, cyclosporine, etanercept, intravenous immunoglobulin, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The papers generated by the search, and their references, were reviewed.

Results

Supportive care is the most universally accepted intervention for SJS/TEN. Specific guidelines differ from the care required for patients with thermal burns. Adjuvant therapies are utilized in most severe cases, but the data are thus far underwhelming and underpowered. Using systemic corticosteroids as sole therapy is not supported. A consensus regarding combined corticosteroids and intravenous immunoglobulin (IVIG) has not been reached. Data regarding IVIG, currently the standard of care for most referral centers, is conflicting. Newer studies regarding cyclosporine and tumor necrosis factor inhibitors are promising, but not powered to provide definitive evidence of efficacy. Data regarding plasmapheresis is equivocal. Thalidomide increases mortality.

Conclusion

Clinicians who manage SJS/TEN should seek to employ interventions with the greatest impact on their patients’ condition. While supportive care measures may seem an obvious aspect of SJS/TEN patient care, providers should understand that these interventions are imperative and that they differ from the care recommended for other critically ill or burn patients. While adjuvant therapies are frequently discussed and debated for hospitalized patients with SJS/TEN, a standardized management approach is not yet clear based on the current data. Therefore, until further data are available, decisions regarding such treatments should be made on a case-by-case basis.

     

Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with pre‐diabetes and diabetes. The KORA Myocardial Infarction Registry

The lowest glycemic threshold for and the risk factors associated with neuropathic pain have not been established. The aim of this study was to determine the prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), normal glucose tolerance (NGT). Subjects aged 25–74 years with diabetes (n=214) and controls matched for age and sex (n=212) from the population‐based KORA (Cooperative Health Research in the Region of Augsburg) Myocardial Infarction Registry were assessed for neuropathic pain by the Michigan Neuropathy Screening Instrument using its pain‐relevant questions and an examination score cutpoint >2. An oral glucose tolerance test was performed in the controls. Among the controls, 61 (28.8%) had IGT (either isolated or combined with IFG), 70 (33.0%) had isolated IFG, and 81 had NGT. The prevalence of neuropathic pain was 21.0% in the diabetic subjects, 14.8% in those with IGT, 5.7% in those with IFG, and 3.7% in those with NGT (overall p<0.001). In the entire population studied (n=426), age, waist circumference, peripheral arterial disease (PAD), and diabetes were independent factors significantly associated with neuropathic pain, while in the diabetic group it was waist circumference, physical activity, and PAD (all p<0.05). In conclusion, the prevalence of neuropathic pain is relatively high among survivors of myocardial infarction with diabetes and IGT compared to those with isolated IFG and NGT. Associated cardiovascular risk factors including abdominal obesity and low physical activity may constitute targets to prevent neuropathic pain in this population.     

The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: A randomized,placebo‐controlled,cross‐over trial

Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam. Objectives: The aim of this study was to test the analgesic effect of levetiracetam in painful polyneuropathy. Methods: This was a randomized, double‐blind, placebo‐controlled, cross‐over trial with levetiracetam 3000 mg/day versus placebo (6‐week treatment periods). Patients with diagnosed polyneuropathy and symptoms for more than 6 months, age between 20 and 80 years, pain intensity of more than 4 on a 0–10‐point numeric rating scale, and pain at least 4 days a week were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6‐point verbal scale. Results: Ninety‐three patients were screened for participation and 39 patients entered the study. Thirty‐five patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.29 versus placebo 2.28, p =0.979), total pain intensity (levetiracetam 5.5 versus placebo 5.3, p =0.293) or any of the other outcome measures (p =0.147–1.00). Conclusion: This study indicates that the anticonvulsant levetiracetam has no clinically relevant effect on painful polyneuropathy.     

Classifying post‐stroke shoulder pain: Can the DN4 be helpful?

The etiology of post‐stroke shoulder pain (PSSP) is largely unclear and may involve both nociceptive and neuropathic mechanisms. No gold standard is present for PSSP diagnosis. The neuropathic pain diagnostic questionnaire (DN4), was originally developed to identify neuropathic pain in the clinical context. In this study we used the DN4 to categorize PSSP patients and compared symptoms and signs suggestive of either nociceptive or neuropathic pain. Pain complaints and sensory functions were compared between patients with chronic PSSP scoring at least four (DN4+, n=9) or less than four (DN4⁻, n=10) on the DN4. Pain was assessed using a numeric rating scale and the McGill pain questionnaire. Sensory functions were assessed using clinical examination and quantitative sensory testing combined with a cold pressor test. Patients classified as DN4+ reported constant pain, higher pain intensity, a higher impact of pain on daily living, more frequent loss of cold sensation, reduced QST thresholds at the unaffected side and increased QST thresholds at the affected side. Notably, several symptoms and signs suggestive of either neuropathic or nociceptive pain corresponded to the subgroups DN4+ and DN4⁻ respectively. However, since the pathophysiological mechanisms remain unclear and none of the sensory signs could be exclusively related to either DN4+ or DN4⁻, PSSP prognosis and treatment should not be solely based on the DN4. Nonetheless, a thorough assessment of neuropathic and nociceptive pain complaints and somatosensory functions should be included in the diagnostic work‐up of PSSP.     

T‐cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site

Summary. Background: Development of neutralizing anti‐factor (F)VIII antibodies (‘inhibitors’) is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. Objectives: The aim of the present study was to identify T‐cell epitopes in FVIII and characterize T‐cell responses in two unrelated hemophilia A subjects sharing F8‐R593C and HLA‐DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T‐cell epitope. Patients/methods: The binding affinities of peptides for recombinant HLA‐DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide‐loaded tetramers. Results: The inhibitor subjects, but not HLA‐matched controls, had high‐avidity HLA‐DRB1*1101‐restricted T‐cell responses against FVIII_589–608, which contains the hemophilic missense site. Antigen‐specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII_592–603. FVIII_589–608 bound with physiologically relevant (micromolar) IC₅₀ values to recombinant DR0101, DR1101 and DR1501 proteins. Conclusions: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild‐type R593 influences inhibitor risk in this hemophilia A sub‐population.     

Antihyperalgesic and analgesic properties of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia

NMDA‐receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti‐hyperalgesic (prevention of central sensitization) properties of the NMDA‐receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40mg p.o.), flupirtine (100mg) or placebo in a double‐blind, randomized, cross‐over study. Pain evoked by intradermal capsaicin injection as well as pain evoked by pinpricks was significantly reduced by neramexane (?22% to ?30% vs. placebo) in the non‐sensitized skin indicating a marked analgesic effect. Moreover, dynamic mechanical allodynia (pain to light touch) was also significantly attenuated by neramexane (?28% vs. placebo). However, static secondary hyperalgesia to pinprick stimuli after capsaicin injection was not significantly reduced (?9% vs. placebo). Flupirtine showed no analgesic or anti‐hyperalgesic effect. Mechanically‐evoked wind up of pain sensation was not affected by any treatment. The results suggests that in a human surrogate model of neurogenic hyperalgesia a single low‐dose of neramexane had a marked analgesic effect in the sensitized and in the non‐sensitized state and thus may be a useful drug to treat the enhanced pain sensitivity in neuropathic pain patients. Its efficacy may be based on analgesia rather than anti‐hyperalgesia or anti‐windup. In contrast, flupirtine showed neither an analgesic nor an anti‐hyperalgesic effect at a dose used for the treatment of postoperative pain.