Mechanisms of disease: mechanism-based classification of neuropathic pain-a critical analysis

Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological mechanisms. Application of this approach in the clinic is problematic, however, owing to a lack of precise tools to assess symptoms and signs, and difficulties in correlating symptoms and signs with mechanisms. Development and validation of diagnostic methods to identify mechanisms, together with pharmacological agents that specifically target these mechanisms, seems to be the most logical and rational way of improving neuropathic pain treatment.     

Neuropathic pain: Peripheral and central mechanisms

Neuropathic pain refers to a specific pain syndrome characterized by pain and sensory abnormalities in body parts that have lost their normal peripheral innervation or sensory representation. They are to be distinguished from other types of pain because of differences in the underlying pathophysiology and treatment. Following a peripheral nerve injury, a cascade of events occurs in primary afferents causing peripheral sensitization. Central sensitization, which is increased responsiveness in central neurons, is usually the result of an increased barrage from the periphery, but may also occur independent of such peripheral input. Again, a series of molecular changes contribute to this central sensitization. These peripheral and central sensitization phenomena in neuropathic pain represent the pathophysiological reason for the beneficial effect of antihyperalgesic treatment in this type of pain. In future, such treatment is likely to be replaced by agents that in a more specific ways attack the pain-generating mechanisms.     

Antihypertensive efficacy of metoprolol XL/Low dose chlorthalidone (6.25 mg) combination: a randomized,comparative study in Indian patients with mild-to-moderate essential hypertension

Objective

High blood pressure is one of the most important risk factors, directly responsible for increasing the cardiovascular morbidity and mortality. The primary objective was to evaluate the efficacy of metoprolol XL/chlorthalidone against metoprolol XL/hydrochlorothiazide with respect to mean fall in systolic and diastolic blood pressure. The secondary objective was to compare the response rates and to evaluate the tolerability of study medications in patients with mild-tomoderate essential hypertension.

Methods

Total 130 eligible patients (65: metoprolol XL 25 mg/chlorthalidone 6.25 mg; 65: metoprolol XL 25 mg/HCTZ 12.5 mg) were enrolled in this randomized, comparative, multicentric, 12-weeks study. Sixty-two patients from each group completed the study. After 4-weeks of treatment, non-responders from chlorthalidone 6.25 mg combination group were shifted to metoprolol XL 50 mg/chlorthalidone 12.5 mg and non-responders from HCTZ 12.5 mg combination group were escalated to metoprolol XL 50 mg/HCTZ 12.5 mg.

Results

The study treatment groups were comparable with respect to demography and baseline disease characteristics. Both the starting therapies were comparable with respect to mean fall in SBP (p = 0.788) and DBP (p = 0.939), and response rates (p = 1.0) after 4-weeks of therapy. Also both the step-up therapies showed similar mean fall in SBP (p = 0.277) and DBP (p = 0.507) at the end of 12-weeks. However, significantly more number of patients from chlorthalidone 12.5 mg/metoprolol XL 50 mg group responded to therapy as compared to that from HCTZ 12.5 mg/metoprolol XL 50 mg group (p = 0.045). All the reported adverse events were of mild-to-moderate intensity. There were no clinically significant trends in electrolytes (Na⁺, K⁺, Cl^-)and fasting blood sugar, evident across the treatment groups.

Conclusion

Chlorthalidone in combination with metoprolol XL is as effective and well tolerated as widely used combination of metoprolol XL/HCTZ, thus providing an alternative therapeutic option.     

五种中药灭阴道毛滴虫体外试验初步研究

本文对５种中药进行了杀灭阴道毛滴虫体外实验的初步研究。结果表明：白头翁、黄柏和青蒿灭虫效果最好，蛇床子和苦参亦有一定的作用。为进一步开发中药防治阴道毛滴虫提供了研究基础资料。     

The magnitude of nocebo effects in pain: A meta-analysis

The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term “nocebo.” Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen’s d and Hedges’ g. The overall magnitude of the nocebo effect was moderate to large (lowest g = 0.62 [0.24–1.01] and highest g = 1.03 [0.63–1.43]) and highly variable (range of g = −0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 [0.39–1.14] and highest g = 1.17 [0.52–1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 [−0.25 to 1.53] and highest g = 0.87 [0.40–1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice.     

Segmental hypersensitivity and spinothalamic function in spinal cord injury pain

The mechanisms underlying central pain following spinal cord injury (SCI) are unsettled. The purpose of the present study was to examine differences in spinothalamic tract function below injury level and evoked pain in incomplete SCI patients with neuropathic pain below injury level (central pain) versus those without such pain. A clinical examination, quantitative sensory testing and magnetic resonance imaging (MRI) were performed in 10 SCI patients with below-level pain and in 11 SCI patients without neuropathic pain. Patients with and without pain had similar reductions of mechanical and thermal detection thresholds below injury level. SCI patients with central pain had sensory hypersensitivity in dermatomes corresponding to the lesion level more frequently than SCI patients without pain, but this may in part be explained by the exclusion of at-level spontaneous pain in the pain-free group. The rostral-caudal extent of the lesion measured by MRI did not differ between the two patient groups, and there were no statistically significant differences in any of the predefined areas of interest on the axial plane images. This study suggests that neuronal hyperexcitability plays a key role in central SCI pain and furthermore - in contrast to previous findings - that loss of spinothalamic functions does not appear to be a predictor for central neuropathic pain in spinal cord injury.     

Receptors for peanut agglutinin (Arachus hypogea) in childhood acute lymphoblastic leukemia: possible clinical significance

The presence of lymphocyte receptors for peanut agglutinin in significant numbers (greater than 15%) was identified on leukemic cells from T-cell acute lymphoblastic leukemia (T-ALL) (3/4), B-cell ALL (B- ALL) (2/4), null cell ALL (8/17), and on normal fetal thymic lymphocytes but not on normal human peripheral blood lymphocytes. Peanut agglutinin (PNA) binding was blocked specifically on leukemia lymphoblasts and thymic lymphocytes by the addition of galactose to the medium. When all immunologic subgroups of ALL are combined, preliminary data suggest that of the 13 ALL patients having greater than 15% PNA- positive lymphoblasts, 8 had relapsed, whereas none of the 12 ALL patients with less than 15% PNA-positive cells have recurrent disease at this time. It is likely that analysis of PNA receptors on ALL lymphoblasts may be a useful adjunct to the existing clinical and immunologic prognostic indicators.