Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.
In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
Central sensitization; inflammatory pain; neuropathic pain; scaffolding protein; heterosynaptic facilitation
The transition from acute to chronic musculoskeletal pain is not well understood. To understand this transition, it is important to know how peripheral and central sensitization are manifested and how they can be assessed. A variety of human pain biomarkers have been developed to quantify localized and widespread musculoskeletal pain. In addition, human surrogate models may be used to induce sensitization in otherwise healthy volunteers. Pain can arise from different musculoskeletal structures (e.g. muscles, joints, ligaments, or tendons), and differentiating the origin of pain from those different structures is a challenge. Tissue specific pain biomarkers can be used to tease these different aspects. Chronic musculoskeletal pain patients in general show signs of local/central sensitization and spread of pain to degrees which correlate to pain intensity and duration. From a management perspective, it is therefore highly important to reduce pain intensity and try to minimize the duration of pain.
Sensitization; hyperalgesia; experimental pain; muscle; joint
Chronic pain is the leading cause of disability in the United States. The transition from acute to persistent pain is thought to arise from maladaptive neuroplastic mechanisms involving three intertwined processes, peripheral sensitization, central sensitization, and descending modulation. Strategies aimed at preventing persistent pain may target such processes. Models for studying preventive strategies include persistent post-surgical pain (PPP), persistent post-trauma pain (PTP) and post-herpetic neuralgia (PHN). Such entities allow a more defined acute onset of tissue injury after which study of the long-term effects is more easily examined. In this review, we examine the pathophysiology, epidemiology, risk factors, and treatment strategies for the prevention of chronic pain using these models. Both pharmacological and interventional approaches are described, as well as a discussion of preventive strategies on the horizon.
Prevention; Chronic; Persistent Post-surgical Pain; Post-traumatic Pain
Chronic pain is a pervasive health care issue affecting over 50 million Americans and costing more than $100 billion dollars annually in lost productivity and health care costs. As a financially and emotionally taxing condition, the families and friends of people with chronic pain, as well as society at large, are affected. Current theory supports the role of biological, psychological, and environmental factors in the etiology, exacerbation, and maintenance of chronic pain. Recently, the specific role of pain-related fear in pain experience has received increasing attention. This article summarizes current understanding of the role of pain-related fear in the onset of acute pain incidents, the transition of acute pain to chronic, and the pain severity and disability of patients with ongoing chronic pain conditions. Treatments demonstrated to reduce pain-related fear are presented, evidence demonstrating their efficacy at reducing disability and pain severity are summarized, and recent criticisms of the fear-avoidance model and future directions are considered.
Fear; Pain; Fear-avoidance; Catastrophizing
We are proposing a unifying theory or law of pain, which states: The origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile. Treatment of pain syndromes should be based on these principles:
Determination of the inflammatory profile of the pain syndromeInhibition or suppression of production of the appropriate inflammatory mediators e.g. with inflammatory mediator blockers or surgical intervention where appropriateInhibition or suppression of neuronal afferent and efferent (motor) transmission e.g. with anti-seizure drugs or local anesthetic blocksModulation of neuronal transmission e.g. with opioid medication
At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization.
inflammation; cytokine; interleukin 1 beta; tumor necrosis factor alpha; sympathetic nerve block; sympathectomy; lumbar block; stellate ganglion; non-steroidal anti-inflammatory drugs (NSAIDs); Steroid; Etanercept; Anakinra; Oxcarbazepine; Ketamine; arthritis; migraine; Complex Regional Pain Syndrome (CRPS); Reflex Sympathetic Dystrophy (RSD); back pain; neck pain; herniated disks; migraine; Fibromyalgia; Interstitial cystitis; Neuropathic pain; Post-stroke pain
Chronic pain has been traditionally defined by pain duration, but this approach has limited empirical support; and does not account for chronic pain’s multidimensionality. This study compared duration-based and prospective approaches to defining chronic pain in terms of their ability to predict future pain course and outcomes for primary care patients with three common pain conditions: back pain (n = 971), headache (n = 1078), or orofacial pain (n = 455). At baseline, their chronic pain was classified retrospectively based on Pain Days in the prior six months and prospectively with a prognostic Risk Score identifying patients with “possible” or “probable” chronic pain. The 0–28 Risk Score was based on pain intensity, pain-related activity limitations, depressive symptoms, number of pain sites, and Pain Days. Pain and behavioral outcomes were assessed at six-month follow-up, and long-term opioid use was assessed two to five years after baseline. Risk Score consistently predicted clinically significant pain at six months better than did Pain Days alone (Area under the Curve of 0.74–0.78 for Risk Score vs. 0.63–0.73 for Pain Days). Risk Score was a stronger predictor of future SF-36 Physical Function, pain-related worry, unemployment, and long-term opioid use than Pain Days alone. Thus, for these three common pain conditions, a prognostic Risk Score had better predictive validity for pain outcomes than did pain duration alone. However, chronic pain appears to be a continuum rather than a distinct class, because long-term pain outcomes are highly variable and inherently uncertain.
chronic pain; back pain; headache; orofacial pain; classification; epidemiology
Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune-derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain.
Fibromyalgia (FM) pain is frequent in the general population but its pathogenesis is only poorly understood. Many recent studies have emphasized the role of central nervous system pain processing abnormalities in FM, including central sensitization and inadequate pain inhibition. However, increasing evidence points towards peripheral tissues as relevant contributors of painful impulse input that might either initiate or maintain central sensitization, or both. It is well known that persistent or intense nociception can lead to neuroplastic changes in the spinal cord and brain, resulting in central sensitization and pain. This mechanism represents a hallmark of FM and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established only minimal nociceptive input is required for the maintenance of the chronic pain state. Additional factors, including pain related negative affect and poor sleep have been shown to significantly contribute to clinical FM pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of FM and other chronic pain syndromes.
Chronic pain is mainly a result of two processes: peripheral and central sensitization, which can result in neuroplastic changes. Previous psychophysical studies suggested a decrease of the so-called pain-inhibiting-pain effect (DNIC) in chronic pain patients. We aimed to study the DNIC effect on the neuronal level using magnetoencephalography and electroencephalography in 12 patients suffering from advanced unilateral knee osteoarthritis (OA). DNIC was induced in patients by provoking the typical OA pain by a slightly hyperextended joint position, while they received short electrical pain stimuli. Although the patients did not report a reduction of electrical pain perception, the cingulate gyrus showed a decrease of activation during provoked OA pain, while activity in the secondary somatosensory cortex did not change. Based on much stronger DNIC induction at comparable intensities of an acute counterirritant pain in healthy subjects this result suggests a deficit of DNIC in OA patients. We suggest that the strength of DNIC is subject to neuronal plasticity of descending inhibitory pain systems and diminishes during the development of a chronic pain condition.
counterirritation; DNIC; osteoarthritis; chronic pain; EEG; MEG
Little is known about the evolution of chronic pain in primary care. Forty five patients with a four week history of musculoskeletal pain were assessed and followed up over 26 weeks by a research nurse using a structured interview and formal assessment instruments. Patients aged 18 to 65 years were recruited on presentation at two semirural Cheshire general practices and subsequently interviewed on a domiciliary visit. Twenty patients (44%) continued to have pain at 26 weeks and these patients were considered to have chronic pain. Nineteen patients had no pain after 12 weeks and a further six had no pain after 26 weeks; these patients together formed the group with acute pain. Comparing the two groups at entry into the study (pain of four weeks' duration) demonstrated significantly higher visual analogue scale scores for intensity of pain (P < 0.01) and a higher incidence of depression (P < 0.01) in the group which subsequently developed chronic pain. In this group, the presence of depression at 12 weeks was associated with higher visual analogue scale scores (P < 0.05) but at 26 weeks scores were similar in depressed and non-depressed patients. The correlation between visual analogue scale score for intensity of pain and the use of passive coping strategies to cope with pain appeared more strongly positive with duration of pain (P < 0.05 at 26 weeks). It is suggested that high pain intensity scores, the presence of depression, and the increasing use of passive coping strategies may be identifiable associations with the development of chronic pain. Areas for further research are identified.
The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
Patients with chronic pain syndromes, like fibromyalgia (FM) complain of widespread pain and tenderness, as well as non-refreshing sleep, cognitive dysfunction, and negative mood. Several lines of evidence implicate abnormalities of central pain processing as contributors for chronic pain, including dysfunctional descending pain inhibition. One form of endogenous pain inhibition, diffuse noxious inhibitory controls (DNIC), has been found to be abnormal in some chronic pain patients and evidence exists for deficient spatial summation of pain, specifically in FM. Similar findings have been reported in patients with localized musculoskeletal pain (LMP) disorders, like neck and back pain. Whereas DNIC reduces pain through activation of nociceptive afferents, vibro-tactile pain inhibition involves innocuous A-beta fiber. To assess whether patients with localized or widespread pain disorders have dysfunctional A-beta related pain inhibition we enrolled 28 normal pain-free controls (NC), 29 FM patients, and 19 subjects with neck or back pain. All received 10 s sensitivity-adjusted noxious heat stimuli to the forearms as test stimuli. To assess endogenous analgesic mechanisms of study subjects, vibro-tactile conditioning stimuli were simultaneously applied with test stimuli either homotopically or heterotopically. Additionally, the effect of distraction on experimental pain was assessed. Homotopic vibro-tactile stimulation resulted in 40% heat pain reductions in all subject groups. Distraction did not seem to affect experimental pain ratings.
Vibro-tactile stimulation effectively recruited analgesic mechanisms not only in NC but also in patients with chronic musculoskeletal pain, including FM. Distraction did not seem to contribute to this analgesic effect.
Analgesia; Fibromyalgia; Chronic pain; Facilitation; Inhibition; Vibration
The intensity of acute and chronic pain depends on interactions between peripheral impulse input and CNS pain mechanisms, including facilitation and inhibition. Whereas tonic pain inhibition is a characteristic of most pain-free individuals, pain facilitation can be detected in many chronic pain patients. The capability to inhibit pain is normally distributed along a wide continuum in the general population and can be used to predict chronic pain. Accumulating evidence suggests that endogenous pain inhibition depends on activation of the prefrontal cortex, periaqueductal gray and rostral ventral medulla. Quantitative sensory test paradigms have been designed to acquire detailed information regarding each individual’s endogenous pain inhibition and facilitation. Such tests include: temporal summation of pain, which is mostly used to assess facilitatory pain modulation by measuring the change in pain perception during a series of identical nociceptive stimuli; and conditioned pain modulation, which tests pain inhibition by utilizing two simultaneously applied painful stimuli (the ‘pain inhibits pain’ paradigm). Considerable indirect evidence seems to indicate that not only increased pain facilitation but also ineffective pain inhibition represents a predisposition for chronic pain. This view is supported by the fact that many chronic pain syndromes (e.g., fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, headache and chronic fatigue syndrome) are associated with hypersensitivity to painful stimuli and reduced endogenous pain inhibition. However, future prospective studies will be necessary to provide definitive evidence for this relationship. Such research would not only provide important information about mechanisms relevant to chronic pain but would also permit identification of individuals at high risk for future chronic pain.
central sensitization; chronic pain; facilitation; fibromyalgia; inhibition; osteoarthritis; pain modulation
Although chronic daily headache (CDH) represents one of the most relevant complaints of patients in headache centers, the mechanisms underlying the chronicization of head pain are poorly understood. Experimental animal models of chronic pain suggest the involvement of a functional disturbance of several neuronal pathways. The disturbances include an abnormal excitability of nociceptive fibers supplying pain-sensitive structures in the brain responsible for peripheral sensitization (chronic neurogenic inflammation), an increased responsiveness of sensory neurons of the dorsal horns in the upper spinal cord and trigeminal nucleus caudalis (central sensitization), and a functional abnormality of facilitating and inhibitory supraspinal pathways. Moreover, based on the experimental chronic pain models, the concepts of hyperalgesia and allodynia, the phenomena of wind-up and kindling, and the suggestion of a long-term potentiation (LTP) inducing a “memory of pain” also in the head have been advocated to explain chronic head pain. However, these hypotheses have been only partially substantiated by robust findings in patients affected by CDH. In the last few years, investigation in patients with biochemical disturbances and neurotransmitter abnormalities in patients with CDH have been undertaken. Certain common mechanisms, but also discrepancies, have been identified between the two principal CDH forms, “ transformed migraine” and chronic tension-type headache. The biochemical and neurotransmitter alterations associated with analgesic and ergotamine abuse, which often is associated with CDH and the more recent triptan misuse, are at the moment only partially known. The most relevant results supporting the alteration of neurotransmitter pathways related to nociception in CDH are reviewed.
Key words Chronic headache; Central sensitization; Neurotransmitter abnormalities; Experimental evidence; Human studies
Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15-20% of women in the United States. Endometriosis is often associated with CPP, however other factors, such as pre-existing or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing.Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, as well as 23 healthy controls. All patients with endometriosis and/or CPP were surgically-confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception including the left thalamus, left cingulategyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis that had no CPP. We conclude thatCPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.
chronic pelvic pain; endometriosis; voxel based morphometry; thalamus; cingulate cortex
Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period.
We have performed a microarray analysis of the rat L4/L5 dorsal root ganglia (DRG), 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour. The results show a set of genes, differentially regulated in the adult DRG, that are principally involved in immune system modulation. A functional consequence of this different immune response to injury is that resident macrophages cluster around the large A sensory neuron bodies in the adult DRG seven days post injury, whereas the macrophages in young DRG remain scattered evenly throughout the ganglion, as in controls.
The results show, for the first time, a major difference in the neuroimmune response to nerve injury in the dorsal root ganglion of young and adult rats. Differential analysis reveals a new set of immune related genes in the ganglia, that are differentially regulated in adult neuropathic pain, and that are consistent with the selective activation of macrophages around adult, but not young large A sensory neurons post injury. These differences may contribute to the reduced incidence of neuropathic pain in infants.
Pain assessment in patients who are unable to verbally communicate with medical staff is a challenging problem in patient critical care. The fundamental limitations in sedation and pain assessment in the intensive care unit (ICU) stem from subjective assessment criteria, rather than quantifiable, measurable data for ICU sedation and analgesia. This often results in poor quality and inconsistent treatment of patient agitation and pain from nurse to nurse. Recent advancements in pattern recognition techniques using a relevance vector machine algorithm can assist medical staff in assessing sedation and pain by constantly monitoring the patient and providing the clinician with quantifiable data for ICU sedation. In this paper, we show that the pain intensity assessment given by a computer classifier has a strong correlation with the pain intensity assessed by expert and non-expert human examiners.
Nursing critically ill patients includes planning and performing safe discharges from Intensive Care Units (ICU) to the general wards. The aim of this study was to obtain a deeper understanding of the main concern in the ICU transitional process—the care before, during, and after the transfer of ICU patients. Interviews were conducted with 35 Swedish nurses and analysed according to grounded theory. The main concern was the nurses' “struggling with a gap.” The “gap” was caused by differences in the altered level of care and contributed to difficulties for nurses encountering an overlap during the transitional care. The categories: sheltering, seeking organizational intertwining and striving for control are related to the core category and were used to generate a theory. The nurses sought improved collaboration, and employed patient-centred routines. They wanted access to necessary tools; they relayed or questioned their own competence and sought assurance of the patients' ability to be transferred. If the nurses felt a loss of control, lack of intertwining and lack of collaboration, they sheltered their patients and themselves. Intertwining was more difficult to perform, but actually even more important to do. With knowledge about ICU transitional care, collaboration, routines, and with an organization that provides an educational environment, the process could be improved.
Collaborating; discharge process; ICU discharge; grounded theory; nursing; transitional care
Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression.
We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs) as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide). Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38.
Our results indicate that MKP-1, the natural regulator of p-p38, mediates resolution of the spinal cord pro-inflammatory milieu induced by peripheral nerve injury, resulting in prevention of chronic mechanical hypersensitivity. We propose that MKP-1 is a potential therapeutic target for pain treatment or prevention.
Phosphatases; MKP-1; Spinal cord; p38; Kinases; Allodynia; Nanoparticle; Nanotechnology
Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways, which reduce synaptic inhibition in inflammatory and neuropathic pain states, have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C–fiber) input to the spinal dorsal horn. We found that endocannabinoids produced upon strong nociceptive stimulation activated CB1 receptors on inhibitory dorsal horn neurons to reduce the synaptic release of GABA and glycine and thus rendered nociceptive neurons excitable by non-painful stimuli. Spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain controlling circuits.
Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. Effective treatment for neuropathic pain is still lacking, due in part to poor understanding of pathological mechanisms at the molecular level. Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury. Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions. In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain.
During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Aδ-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-α, IL-1β), PGE2, bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Nav1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source.
Peripheral sensitization; dorsal root ganglion; inflammatory pain; neuropathic pain; MAP kinases; neural plasticity
Intensive care unit (ICU) admission may connote an elevated risk of unintentional chronic medication discontinuation because of its focus on acute illnesses and the multiple care transitions.
To determine the proportion of patients discharged from the ICU whose previously prescribed chronic medications were unintentionally discontinued during their hospitalization.
DESIGN AND PARTICIPANTS
Hospital records of consecutive ICU discharges at 1 academic and 2 community hospitals in Toronto, Canada, throughout 2002 were reviewed. Eligible patients were prescribed at least 1 of 6 medication groups before hospitalization: (1) HMG co-A reductase inhibitors (statins); (2) antiplatelets/anticoagulants (aspirin, clopidogrel, ticlopidine, warfarin); (3) l-thyroxine; (4) non-prn inhalers (anticholinergic, β-agonist, or steroid); (5) acid-suppressing drugs (H2 antagonists and proton pump inhibitors); and (6) allopurinol.
Use of explicit criteria to assess the proportion of patients whose previously prescribed chronic medications were unintentionally discontinued at hospital discharge.
A total of 1,402 charts were eligible for the study and 834 had prescriptions for at least 1 of the medication groups. Thirty-three percent (251/834) of patients had 1 or more of their chronic medications omitted at hospital discharge. Multivariable logistic regression analysis found that patients from the academic hospital (adjusted odds ratio [OR]=0.70, 95% confidence interval [CI] 0.49 to 1.0) and those with medical diagnoses (adjusted OR=0.48, 95% CI 0.31 to 0.75) had a decreased risk for chronic medication discontinuation.
Patients discharged from the ICU often leave the hospital without note of their previously prescribed chronic medications. Careful review of medication lists at ICU discharge could avoid potential adverse outcomes related to unintentional discontinuation of chronic medications at hospital discharge.
drug discontinuation; continuity of care; chronic medications; patient safety; intensive care unit
Patients in the intensive care unit (ICU) who require mechanical ventilation due to acute respiratory failure also frequently require the administration of sedative agents. The need for sedation arises both from patient anxiety due to the loss of personal control and the unfamiliar and intrusive environment of the ICU, and also due to pain or other variants of noxious stimuli. While physicians select the agent(s) used for sedation and cardiovascular function, the actual administration of these agents is the responsibility of the nursing staff. If clinical decision support systems and closed-loop control systems could be developed for critical care monitoring and lifesaving interventions as well as the administration of sedation and cardiopulmonary management, the ICU nurse could be released from the intense monitoring of sedation, allowing her/him to focus on other critical tasks. One particularly attractive strategy is to utilize the knowledge and experience of skilled clinicians, capturing explicitly the rules expert clinicians use to decide on how to titrate drug doses depending on the level of sedation. In this paper, we extend the deterministic rule-based expert system for cardiopulmonary management and ICU sedation framework presented in  to a stochastic setting by using probability theory to quantify uncertainty and hence deal with more realistic clinical situations.
Bayesian networks; cardiopulmonary management; decision support; expert system; intensive care unit (ICU) sedation; respiratory management; rule-based expert system
Mechanisms underlying chronic pain differ from those underlying acute pain. In chronic pain states, central nervous system (CNS) factors appear to play particularly prominent roles. In the absence of anatomical causes of persistent pain, medical sub-specialties have historically applied wide-ranging labels (e.g. fibromyalgia -FM, irritable bowel syndrome, interstitial cystitis, somatization) for what now is emerging as a single common set of CNS processes. The hallmark of these “centrally-driven” pain conditions is a diffuse hyperalgesic state identifiable using experimental sensory testing, and corroborated by functional neuroimaging. The characteristic symptoms of these central pain conditions include multifocal pain, fatigue, insomnia, memory difficulties, and a higher rate of co-morbid mood disorders. In contrast to acute and “peripheral” pain states that are responsive to NSAIDs and opioids, central pain conditions respond best to CNS neuromodulating agents such as serotonin-norepinephrine re-uptake inhibitors (SNRIs) and anticonvulsants.
Central pain; Peripheral pain; Chronic pain; Neuroimaging; Osteoarthritis; Fibromyalgia