Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

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Central sensitization: implications for the diagnosis and treatment of pain.

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

The National Academy of Sciences through its Institute of Medicine (IOM) has produced a major scholarly assessment of pain in America. This document is a tremendous contribution to the evolving nec...

Relieving pain in america: a blueprint for transforming prevention, care, education, and research

Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

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Cell Biology of Ischemia/Reperfusion Injury

This review is a critical summary of research examining gender variations in clinical pain experience. Gender-comparative pain research was identified through Medline and Psychlit searches and references obtained from bibliographies of pertinent papers and books. Review of this research demonstrates that women are more likely than men to experience a variety of recurrent pains. In addition, many women have moderate or severe pains from menstruation, pregnancy and childbirth. In most studies, women report more severe levels of pain, more frequent pain and pain of longer duration than do men. Women may be at greater risk for pain-related disability than men but women also respond more aggressively to pain through health related activities. Women may be more vulnerable than men to unwarranted psychogenic attributions by health care providers for pain. Underlying biological mechanisms of pain and the contribution of psychological and social factors as they contribute to the meaning of pain for women and men warrant greater attention in pain research.

Gender variations in clinical pain experience.

alpha(2)-adrenergic agonists for regional anesthesia - A clinical review of clonidine (1984-1995)

Neutrophil-to-lymphocyte ratio (NLR) has proven its prognostic value in cardiovascular diseases, infections, inflammatory diseases and in several types of cancers. However, no cut-off has been proposed on the basis of reference values coming from healthy population. Routine blood samples were obtained (n = 413) from workers (age: median 38, range: 21–66 years) involved in a health care prevention program, to determine means, standard deviations (SDs), 95% confidence intervals (95% CI), percentiles P2.5 and P97.5. A second independent sample of healthy volunteers is compared (n = 29). The mean NLR is 1.65 [±1.96 SD: 0.78–3.53] (95% CI [0.75–0.81] and [3.40–3.66]). In the second cohort (healthy control), the NLR values are in the same range, whichever the used analyzer. No NLR assessed in the validation series is out of the proposed limits. We have identified that the normal NLR values in an adult, non-geriatric, population in good health are between 0.78 and 3.53. These data will help to define the normal values of the NLR.

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What is the normal value of the neutrophil-to-lymphocyte ratio?

We investigated whether intraoperative 'subanesthetic doses' of ketamine have a postoperative anti-hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. They were randomly assigned to receive no ketamine (group 1), i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5). All i.v. and epidural analgesics were stopped at the end of surgery and patients were connected to an i.v. morphine patient-controlled analgesia (PCA) device. Short-term postoperative analgesia (72 h) was assessed by pain visual analog scale scores at rest, cough, and movements as well as by PCA requirements. Wound mechanical hyperalgesia was evaluated and residual pain was assessed by asking the patients at 2 weeks, and 1, 6, and 12 months. The area of hyperalgesia and morphine PCA requirements were significantly reduced in group 3. These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route.

'Balanced analgesia' in the perioperative period: is there a place for ketamine?

BACKGROUND: As a broader definition of preemptive analgesia, preventive analgesia aims to prevent the sensitization of central nervous system, hence the development of pathologic pain after tissular injury. To demonstrate benefits from preventive treatment, objective measurement of postoperative pain such as wound hyperalgesia and persistent pain should be evaluated. The current study assessed the role and timing of epidural analgesia in this context. METHODS: In a randomized, double-blinded trial, 85 patients scheduled to undergo neoplastic colonic resection were included. All the patients received a thoracic epidural catheter, systemic ketamine at a antihyperalgesic dose, and general anesthesia. Continuous infusion of analgesics belonging to the same class was administered by either intravenous or epidural route before incision until 72 h after surgery. Patients were allocated to four groups to receive intraoperative intravenous lidocaine-sufentanil-clonidine or epidural bupivacaine-sufentanil-clonidine followed postoperatively by either intravenous (lidocaine-morphine-clonidine) or epidural (bupivacaine-sufentanil-clonidine) patient-controlled analgesia. Postoperative pain scores (visual analog scale), analgesic consumption, wound area of punctuate hyperalgesia, residual pain, and analgesics needed from 2 weeks until 12 months were recorded. RESULTS: Analgesic requirements, visual analog scale scores, and area of hyperalgesia were significantly higher in the intravenous treatment group (intravenous-intravenous), and more patients reported residual pain from 2 weeks until 1 yr (28%). Although postoperative pain measurements did not differ, postoperative epidural treatment (intravenous-epidural) was less effective to prevent residual pain at 1 yr (11%; P = 0.2 with intravenous-intravenous group) than intraoperative one (epidural-epidural and epidural-intravenous groups) (0%; P = 0.01 with intravenous-intravenous group). CONCLUSION: Combined with an antihyperalgesic dose of ketamine, intraoperative epidural analgesia provides effective preventive analgesia after major digestive surgery.

Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery.

Background: Dynamic variables predict fluid responsiveness and may improve fluid management during surgery. We investigated whether displaying the variability in the pulse oximeter plethysmogram (pleth variability index; PVI) would guide intraoperative fluid management and improve circulation as assessed by lactate levels. Methods: Eighty-two patients scheduled for major abdominal surgery were randomized into 2 groups to compare intraoperative PVI-directed fluid management (PVI group) versus standard care (control group). After the induction of general anesthesia, the PVI group received a 500-mL crystalloid bolus and a crystalloid infusion of 2 mL . kg(-1) . h(-1). Colloids of 250 mL were administered if the PVI was >13%. Vasoactive drug support was given to maintain the mean arterial blood pressure above 65 mm Hg. In the control group, an infusion of 500 mL of crystalloids was followed by fluid management on the basis of fluid challenges and their effects on mean arterial blood and central venous pressure. Perioperative lactate levels, hemodynamic data, and postoperative complications were recorded prospectively. Results: Intraoperative crystalloids and total volume infused were significantly lower in the goal-directed PVI group. Lactate levels were significantly lower in the PVI group during surgery and 48 hours after surgery (P < 0.05). Conclusions: PVI-based goal-directed fluid management reduced the volume of intraoperative fluid infused and reduced intraoperative and postoperative lactate levels.

/pdf/goal-directed-fluid-management-based-on-the-pulse-oximeter-1r479fcepb.pdf

Marc De Kock

Papers

alpha(2)-adrenergic agonists for regional anesthesia - A clinical review of clonidine (1984-1995)

What is the normal value of the neutrophil-to-lymphocyte ratio?

'Balanced analgesia' in the perioperative period: is there a place for ketamine?

Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery.

Goal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid management