Chronic opioid therapy and opioid tolerance: a new hypothesis.

Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI-VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed.

Apparent treatment-resistant hypertension and chronic kidney disease: another cardiovascular-renal syndrome?

To identify patients at increased risk of cardiovascular (CV) outcomes, apparent treatment-resistant hypertension (aTRH) is defined as having a blood pressure above goal despite the use of 3 or more antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. Recent epidemiologic studies in selected populations estimated the prevalence of aTRH as 10% to 15% among patients with hypertension and that aTRH is associated with elevated risk of CV and renal outcomes. Additionally, aTRH and CKD are associated. Although the pathogenesis of aTRH is multifactorial, the kidney is believed to play a significant role. Increased volume expansion, aldosterone concentration, mineralocorticoid receptor activity, arterial stiffness, and sympathetic nervous system activity are central to the pathogenesis of aTRH and are targets of therapies. Although diuretics form the basis of therapy in aTRH, pathophysiologic and clinical data suggest an important role for aldosterone antagonism. Interventional techniques, such as renal denervation and carotid baroreceptor activation, modulate the sympathetic nervous system and are currently in phase III trials for the treatment of aTRH. These technologies are as yet unproven and have not been investigated in relationship to CV outcomes or in patients with CKD.

Effects of chronic mild traumatic brain injury on white matter integrity in iraq and afghanistan war veterans

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. © 2012 Wiley Periodicals, Inc.

The effectiveness of low-level laser therapy for nonspecific chronic low back pain: a systematic review and meta-analysis.

BACKGROUND: In recent decades, low-level laser therapy (LLLT) has been widely used to relieve pain caused by different musculoskeletal disorders. Though widely used, its reported therapeutic outcomes are varied and conflicting. Results similarly conflict regarding its usage in patients with nonspecific chronic low back pain (NSCLBP). This study investigated the efficacy of low-level laser therapy (LLLT) for the treatment of NSCLBP by a systematic literature search with meta-analyses on selected studies. METHOD: MEDLINE, EMBASE, ISI Web of Science and Cochrane Library were systematically searched from January 2000 to November 2014. Included studies were randomized controlled trials (RCTs) written in English that compared LLLT with placebo treatment in NSCLBP patients. The efficacy effect size was estimated by the weighted mean difference (WMD). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). RESULTS: Of 221 studies, seven RCTs (one triple-blind, four double-blind, one single-blind, one not mentioning blinding, totaling 394 patients) met the criteria for inclusion. Based on five studies, the WMD in visual analog scale (VAS) pain outcome score after treatment was significantly lower in the LLLT group compared with placebo (WMD = -13.57 [95 % CI = -17.42, -9.72], I(2) = 0 %). No significant treatment effect was identified for disability scores or spinal range of motion outcomes. CONCLUSIONS: Our findings indicate that LLLT is an effective method for relieving pain in NSCLBP patients. However, there is still a lack of evidence supporting its effect on function.

A screw microdrive for adjustable chronic unit recording in monkeys.

A screw microdrive is described that attaches to the grid system used for recording single neurons from brains of awake behaving monkeys. Multiple screwdrives can be mounted on a grid over a single cranial opening. This method allows many electrodes to be implanted chronically in the brain and adjusted as needed to maintain isolation. rights reserved.

The Application of an Exogenous Linear and Radial Electrical Field to an In Vitro Chronic Diabetic Ulcer Model for Evaluation as a Potential Treatment

Chronic diabetic ulcers affect approximately 15% of patients with diabetes worldwide. Currently, applied electric fields are being investigated as a reliable and cost-effective treatment. This in vitro study aimed to determine the effects of a constant and spatially variable electric field on three factors: endothelial cell migration, proliferation, and angiogenic gene expression. Results for a constant electric field of 0.01 V demonstrated that migration at short time points increased 20-fold and proliferation at long time points increased by a factor of 1.40. Results for a spatially variable electric field did not increase directional migration, but increased proliferation by a factor of 1.39 and by a factor of 1.55 after application of 1.00 V and 0.01 V, respectively. Both constant and spatially variable applied fields increased angiogenic gene expression. Future research that explores a narrower range of intensity levels may more clearly identify the optimal design specifications of a spatially variable electric field.