Nociceptive Function Research Articles

Rat Sciatic Nerve Reconstruction Across a 30 mm Defect Bridged by an Oriented Porous PHBV Tube With Schwann Cell as Artificial Nerve Graft

An oriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit has been used to evaluate its efficiency based on the promotion of peripheral nerve regeneration in rats. The oriented porous micropatterned artificial nerve conduit was designed onto the micropatterned silicon wafers, and then their surfaces were modified with oxygen plasma to increase cell adhesion. The designed conduits were investigated by cell culture analyses with Schwann cells (SCs). The conduits were implanted into a 30 mm gap in sciatic nerves of rats. Four months after surgery, the regenerated nerves were monitored and evaluated by macroscopic assessments and histology and behavioral analyses. Results of cellular analyses showed suitable properties of designed conduit for nerve regeneration. The results demonstrated that in the polymeric graft with SCs, the rat sciatic nerve trunk had been reconstructed with restoration of nerve continuity and formatted nerve fibers with myelination. Histological results demonstrated the presence of Schwann and glial cells in regenerated nerves. Functional recovery such as walking, swimming, and recovery of nociceptive function was illustrated for all the grafts especially conduits with SCs. This study proves the feasibility of the artificial nerve graft filled with SCs for peripheral nerve regeneration by bridging a longer defect in an animal model.

Caenorhabditis elegans nicotinic acetylcholine receptors are required for nociception

Polymodal nociceptors sense and integrate information on injurious mechanical, thermal, and chemical stimuli. Chemical signals either activate nociceptors or modulate their responses to other stimuli. One chemical known to activate or modulate responses of nociceptors is acetylcholine (ACh). Across evolution nociceptors express subunits of the nicotinic acetylcholine receptor (nAChR) family, a family of ACh-gated ion channels. The roles of ACh and nAChRs in nociceptor function are, however, poorly understood. Caenorhabditis elegans polymodal nociceptors, PVD, express nAChR subunits on their sensory arbor. Here we show that mutations reducing ACh synthesis and mutations in nAChR subunits lead to defects in PVD function and morphology. A likely cause for these defects is a reduction in cytosolic calcium measured in ACh and nAChR mutants. Indeed, overexpression of a calcium pump in PVD mimics defects in PVD function and morphology found in nAChR mutants. Our results demonstrate, for the first time, a central role for nAChRs and ACh in nociceptor function and suggest that calcium permeating via nAChRs facilitates activity of several signaling pathways within this neuron.

Hyperexcitable C nociceptors in fibromyalgia

To test the hypothesis that peripheral C nociceptor function may be abnormal in fibromyalgia and that C nociceptor dysfunction may contribute to the symptoms reported by these patients. Microneurography was used to record C nociceptors of 30 female patients meeting criteria for fibromyalgia and compared with recordings from 17 female patients with small-fiber neuropathy and 9 female controls. We obtained stable recordings of 186 C nociceptors in the fibromyalgia group, 114 from small-fiber neuropathy patients, and 66 from controls. The mechanosensitive nociceptors in the fibromyalgia patients behaved normally, but the silent nociceptors in 76.6% of fibromyalgia patients exhibited abnormalities. Spontaneous activity was detected in 31% of silent nociceptors in fibromyalgia, 34% in small-fiber neuropathy, and 2.2% in controls. Sensitization to mechanical stimulation was found in 24.2% of silent nociceptors in fibromyalgia, 22.7% in small-fiber neuropathy, and 3.7% in controls. Abnormally high slowing of conduction velocity when first stimulated at 0.25Hz was more common in fibromyalgia. We show for the first time that the majority of fibromyalgia patients have abnormal C nociceptors. Many silent nociceptors exhibit hyperexcitability resembling that in small-fiber neuropathy, but high activity-dependent slowing of conduction velocity is more common in fibromyalgia patients, and may constitute a distinguishing feature. We infer that abnormal peripheral C nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain and tenderness suffered by patients with fibromyalgia.

Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H

The link between sodium channel Nav1.7 and pain has been strengthened by identification of gain-of-function mutations in patients with inherited erythromelalgia (IEM), a genetic model of neuropathic pain in humans. A firm mechanistic link to nociceptor dysfunction has been precluded because assessments of the effect of the mutations on nociceptor function have thus far depended on electrophysiological recordings from dorsal root ganglia (DRG) neurons transfected with wild-type (WT) or mutant Nav1.7 channels, which do not permit accurate calibration of the level of Nav1.7 channel expression. Here, we report an analysis of the function of WT Nav1.7 and IEM L858H mutation within small DRG neurons using dynamic-clamp. We describe the functional relationship between current threshold for action potential generation and the level of WT Nav1.7 conductance in primary nociceptive neurons and demonstrate the basis for hyperexcitability at physiologically relevant levels of L858H channel conductance. We demonstrate that the L858H mutation, when modeled using dynamic-clamp at physiological levels within DRG neurons, produces a dramatically enhanced persistent current, resulting in 27-fold amplification of net sodium influx during subthreshold depolarizations and even greater amplification during interspike intervals, which provide a mechanistic basis for reduced current threshold and enhanced action potential firing probability. These results show, for the first time, a linear correlation between the level of Nav1.7 conductance and current threshold in DRG neurons. Our observations demonstrate changes in sodium influx that provide a mechanistic link between the altered biophysical properties of a mutant Nav1.7 channel and nociceptor hyperexcitability underlying the pain phenotype in IEM.

Promoting nerve regeneration in a neurotmesis rat model using poly(DL-lactide-ε-caprolactone) membranes and mesenchymal stem cells from the Wharton's jelly: in vitro and in vivo analysis.

In peripheral nerves MSCs can modulate Wallerian degeneration and the overall regenerative response by acting through paracrine mechanisms directly on regenerating axons or upon the nerve-supporting Schwann cells. In the present study, the effect of human MSCs from Wharton's jelly (HMSCs), differentiated into neuroglial-like cells associated to poly (DL-lactide-ε-caprolactone) membrane, on nerve regeneration, was evaluated in the neurotmesis injury rat sciatic nerve model. Results in vitro showed successful differentiation of HMSCs into neuroglial-like cells, characterized by expression of specific neuroglial markers confirmed by immunocytochemistry and by RT-PCR and qPCR targeting specific genes expressed. In vivo testing evaluated during the healing period of 20 weeks, showed no evident positive effect of HMSCs or neuroglial-like cell enrichment at the sciatic nerve repair site on most of the functional and nerve morphometric predictors of nerve regeneration although the nociception function was almost normal. EPT on the other hand, recovered significantly better after HMSCs enriched membrane employment, to values of residual functional impairment compared to other treated groups. When the neurotmesis injury can be surgically reconstructed with an end-to-end suture or by grafting, the addition of a PLC membrane associated with HMSCs seems to bring significant advantage, especially concerning the motor function recovery.

Chapter 34 - Painful neuropathy: Mechanisms

Painful neuropathy, like the other complications of diabetes, is a growing healthcare concern. Unfortunately, current treatments are of variable efficacy and do not target underlying pathogenic mechanisms, in part because these mechanisms are not well defined. Rat and mouse models of type 1 diabetes are frequently used to study diabetic neuropathy, with rats in particular being consistently reported to show allodynia and hyperalgesia. Models of type 2 diabetes are being used with increasing frequency, but the current literature on the progression of indices of neuropathic pain is variable and relatively few therapeutics have yet been developed in these models. While evidence for spontaneous pain in rodent models is sparse, measures of evoked mechanical, thermal and chemical pain can provide insight into the pathogenesis of the condition. The stocking and glove distribution of pain tantalizingly suggests that the generator site of neuropathic pain is found within the peripheral nervous system. However, emerging evidence demonstrates that amplification in the spinal cord, via spinal disinhibition and neuroinflammation, and also in the brain, via enhanced thalamic activity or decreased cortical inhibition, likely contribute to the pathogenesis of painful diabetic neuropathy. Several potential therapeutic strategies have emerged from preclinical studies, including prophylactic treatments that intervene against underlying mechanisms of disease, treatments that prevent gains of nociceptive function, treatments that suppress enhancements of nociceptive function, and treatments that impede normal nociceptive mechanisms. Ongoing challenges include unraveling the complexity of underlying pathogenic mechanisms, addressing the potential disconnect between the perceived location of pain and the actual pain generator and amplifier sites, and finding ways to identify which mechanisms operate in specific patients to allow rational and individualized choice of targeted therapies.

Multiple impairments of cutaneous nociceptor function by adriamycin

Multiple impairments of cutaneous nociceptor function by adriamycin

Effects of opioids on local anesthesia in the rat: a codeine and tramadol study

Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain.

16. Processing of nociceptive input in schizophrenic patients: Preliminary results

According to previous studies schizophrenic patients have a reduced perception of pain. We aimed at assessing pain thresholds and nociceptive pathway function in schizophrenic patients by using Quantitative Sensory Testing (QST) and Laser Evoked Potentials (LEPs). We planned to enroll 30 patients with a diagnosis of schizophrenia and 30 age and sex matched healthy controls. At present we collected 8 schizophrenic patients and 10 healthy control. All subjects underwent QST and right hand LEPs. Although QST parameters did not show statistical significance between schizophrenic patients and normal controls, the cold pain threshold approached the statistical significance ( P = 0.08, unpaired t -test). Conversely the amplitude of all LEP components was significantly lower in patients than in controls ( P < 0.05). These preliminary data suggest that schizophrenic patients have an abnormal processing of nociceptive input. These abnormalities might reflect a dopaminergic dysfunction.

Efficacy of nanofibrous conduits in repair of long-segment sciatic nerve defects.

Our previous studies have histomorphologically confirmed that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) conduit can be used to repair 30-mm-long sciatic nerve defects. However, the repair effects on rat behaviors remain poorly understood. In this study, we used nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) conduit and autologous sciatic nerve to bridge 30-mm-long rat sciatic nerve gaps. Within 4 months after surgery, rat sciatic nerve functional recovery was evaluated per month by behavioral analyses, including toe out angle, toe spread analysis, walking track analysis, extensor postural thrust, swimming test, open-field analysis and nociceptive function. Results showed that rat sciatic nerve functional recovery was similar after nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) conduit and autologous nerve grafting. These findings suggest that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) conduit is suitable in use for repair of long-segment sciatic nerve defects.

Behavioral evaluation of regenerated rat sciatic nerve by a nanofibrous PHBV conduit filled with Schwann cells as artificial nerve graft

The aim of this study is to develop a nanofibrous polymeric nerve conduit with Schwann cells (SCs) and to evaluate its efficiency on the promotion of functional and locomotive activities in rats. The conduits were implanted into a 30-mm gap in the sciatic nerves of the rats. Four months after surgery, the rats were monitored and evaluated by behavioral analyses such as toe out angle, toe spreading analysis, walking track analysis, extensor postural thrust, open-field analysis, swimming test and nociceptive function, four months post surgery. Four months post-operatively, the results from behavioral analyses demonstrated that in the grafted groups especially in the grafted group with SCs, the rat sciatic nerve trunk had been reconstructed with functional recovery such as walking, swimming and recovery of nociceptive function. This study proves the feasibility of artificial conduit with SCs for nerve regeneration by bridging a longer defect in the rat model.

SAT0311 A Randomized Double-Blind Control Trial of Intra-Articular Hyaluronic Acid:Botulinum Toxin Type a Versus Placebo for Mild to Moderate Knee OA

BackgroundMild to moderate osteoarthritis (OA) knee pain is often poorly controlled despite recommendations of efficacious therapy. These are compounding in the fact that many patients are either intolerant to some...

Migraine et hypothalamus

Migraine is a complex brain disease. The “generator” of the migrainous attacks remains a subject of debate, but the hypothalamus, with its multiple connections with the other parts of the central nervous system and its controls on the pituitary gland and the autonomic nervous system, is a very serious candidate. Many of the premonitory symptoms of migraine attacks find their origin in the hypothalamus. The hormonal changes which occur during feminine genital life and which impact on the life of the migrainous women have their origin in the hypothalamus. The hypothalamus exerts control over the balance between the parasympathetic and orthosympathetic systems. Orexine, hormones originating in the hypothalamic, are involved in sleep regulation, thermoregulation and neuroendocrine and nociceptive functions. They could play a crucial role in the origin of the migrainous attack and might explain the influence of sleep, eating habits and excessive weight in the occurrence of attacks. Hypothalamic cerebral activation via H2 15OPET activity, suspected by clinical and experimental arguments as a possible trigger for migraine, has been demonstrated during spontaneous attacks. However, no conclusion can be made however as to whether this activation is the cause or the consequence of the migrainous pain.

Discriminative sensory characteristics of the lateral femoral cutaneous nerve after mepivacaine-induced block

Background and objectivesUnmyelinated C-fibres comprise the largest group of somatic afferents and have demonstrated a crucial role not only in the perception of high-threshold mechanically, thermally or chemically induced pain, but also in non-harmful low-threshold mechanical stimuli [1,2]. The objective of our study was to characterize differential sensitivity changes of C-fibre related subclasses of high-threshold and low-threshold polymodal nociceptors and low-threshold mechanoreceptors to the local anaesthetic (LA) mepivacaine during nerve block of the purely sensory lateral femoral cutaneous nerve (LFCN) in human. We assumed a diverse response of different classes of afferents to the two different concentrations of the LA mepivacaine (Scandicaine). MethodsIn a double-blind randomized experimental setting, an ultrasound-guided nerve block of the LFCN was performed in 10 healthy male subjects, each with two different concentrations of mepivacaine (0.5 and 1%). Responsiveness of afferent nerve fibres to different noxious and non-noxious stimuli was tested by Quantitative Sensory Testing (QST) 30, 180, and 300min after nerve block. Both LA concentrations of mepivacaine were compared for time course of the areas of anaesthesia for the tested sensory modalities. ResultsInitial extension of anaesthetic areas at 30min did not differ between both LA concentrations. At 180min only the anaesthetic areas to nociceptive stimuli were reduced at the site of lower mepivacaine injection (260mN: 204mm2 (18; 244; median difference and 95% confidence interval; p<0.05), heat: 276mm2 (3; 305)). In contrast, no significant differences were found between the two concentration when non-nociceptive stimuli were used (100mN: 187mm2 (4; 240), p>0.05, brush: 159mm2 (−59; 202)). ConclusionEqual initial sizes of anaesthesia areas for all sensory modalities can be explained by supramaximal perineural LA molecule concentration in both administered mepivacaine dosages. Upon washout of the LA nociceptive function is restored faster as compared to non-nociceptive sensation and higher concentration of the LA are required to maintain the analgesia. Quantitative sensory testing is able to detect different susceptibility of low threshold mechanosensors and subtypes of nociceptive C-fibres to mepivacaine. Using painful mechanical, heat and electrical stimulation different classes of nociceptors will be activated. The analgesic areas to electrical stimulation were particularly small; one might therefore hypothesize that the proposed protocol allows to also differentiate mechano-insensitive (“silent”) and mechanosensitive (“polymodal”) nociceptors. ImplicationsQST is a non-invasive method to functionally examine sensory modalities and their pharmacological modulation in humans. The method is sufficiently sensitive to differentiate the analgesic properties of mepivacaine at 0.5 and 1% and might also be adequate to different classes of nociceptors. Further development of nociceptive stimuli including supra-threshold encoding characteristics will enable to investigate peripheral analgesic effects more specifically and thus might help to design new analgesics with preferential effect on high frequency discharge of nociceptors.

Experimental hypothyroidism during pregnancy affects nociception and locomotor performance of offspring in rats

Thyroid hormones (THs) play a crucial role in the development of several organic systems. An adequate support of maternal THs may be required to ensure a normal nociceptive function of offspring into adulthood. We investigated the impact of experimental gestational hypothyroidism (EGH) on nociceptive threshold and motor performance in the offspring at different post-natal days (PND) in both male and female rats. EGH was induced by the administration of 0.02% methimazole (MMI) in the drinking water from the ninth day of gestation until birth. The offspring from MMI-treated dams (OMTDs) or from water-treated dams (OWTDs) were assessed for thermal and mechanical nociception using the tail-flick test and von Frey filaments, respectively. Both rota-rod and grip strength were used to assess motor function. OMTD had reduced thermal (p<0.05) but not mechanical threshold at all studied ages (60 and 120 PND). Sixty-day-old OMTD presented reduced latency to the tail-flick test (p=0.01). Grip strength in 120-day-old OMTD was reduced (p<0.01). However, only male OMTD presented a lower locomotor performance on the rota-rod test when analysed on the 60th PND (p<0.01). EGH promotes hypersensitivity to noxious thermal but not mechanical stimulus. Moreover, motor force is similarly reduced in male and female OMTDs, whereas motor performance is reduced only in mature male OMTD, suggesting the presence of a protective factor in females.

Axotomy‐induced changes in activity‐dependent slowing in peripheral nerve fibres: Role of hyperpolarization‐activated/HCN channel current

Slowing refers to the gradual decrease in conduction velocity evoked by repetitive electrical stimuli. The underlying mechanisms are still poorly understood, and its physiological/pathological relevance scarcely discussed; however, changes in axonal conduction properties might unmask abnormal nociceptor function and alter the encoding time window at the spinal cord. Here, we characterized and compared the slowing in isolated units recorded from intact and axotomized saphenous nerves from mice, in vitro. We evaluated the role of hyperpolarization-activated/HCN channel current, Ih , in the generation of slowing, by examining the effect of the specific Ih blocker ZD7288. Based on their degree of slowing, intact C-fibres were classified as presumed nociceptors or non-nociceptors (>13% or <7% latency increase, respectively). Upon ZD7288 treatment, slowing was significantly augmented in 19/25 of the presumed C-nociceptors. In nerve-end neuromas, axotomized C-fibres could not be classified by their degree of slowing, which, in addition, was unrelated to the presence of ectopic mechanosensitivity. Axotomized fibres showed a ∼2.5-fold reduction in their slowing as compared with intact units and the effects of ZD7288 were more prominent, both in magnitude and percentage of sensitive fibres. Interestingly, in control conditions, all fibres sensitive to ZD7288 were more resistant to slowing. Under our experimental conditions, slowing seems largely dependent on functional Ih . The marked decrease in slowing after axotomy in C-fibres fits with the increased expression of functional hyperpolarization-activated/HCN channel current and may underlie the analgesic effects of the specific Ih blocker ZD7288 previously described in neuropathic pain models.

Effects of Topical Capsaicin on Cutaneous Innervation: Implications for Pain Management

Changes in cutaneous innervation are a hallmark of neuropathic pain syndromes. Although in few cases the density of cutaneous innervation increases in painful areas, for the most part the density of nociceptive sensory nerve endings decreases and the degree of deinnervation seems to correlate with the severity of pain. In combination with tests for nociceptor function, immunostaining for protein gene product 9.5 (PGP 9.5) is commonly used as diagnostic tool to indicate these pathophysiological changes in cutaneous innervation. However, sole reliance on PGP 9.5 may underestimate the presence of regenerating sensory nerve terminals or fail to capture changes in the expression of proteins such as ion channels or receptors. Topical capsaicin consistently reduces intra-epidermal nerve fiber density assayed via PGP 9.5, and also increases thresholds for activation of some thermoreceptors. The mechanism of action involves a highly localized insult to cutaneous nociceptors mediated by activation of TRPV1 and calcium overload, and perhaps even a direct toxicity to mitochondria. It is possible that topical capsaicin and lidocaine share an ability to reduce cutaneous innervation by inducing localized toxicity in mitochondria-rich nociceptive terminals. Overall, the high local concentrations of drugs and even excipients delivered by topical analgesics into the skin may be able to activate secondary pharmacodynamic processes. Optimizing topical formulations of capsaicin or other analgesics to maximize pain relief with the fewest adverse effects is not a simple matter of varying drug concentration, and it is highly questionable whether ‘bioequivalence’ could ever be based simply upon equivalent cutaneous drug delivery.

Role of a novel nociceptor autocrine mechanism in chronic pain

We have previously shown, in the rat, that neuropathic and inflammatory events produce a neuroplastic change in nociceptor function whereby a subsequent exposure to a proinflammatory mediator (e.g. prostaglandin E2 ; PGE2 ) produces markedly prolonged mechanical hyperalgesia. While the initial approximately 30min of this prolonged PGE2 hyperalgesia remains PKA-dependent, it subsequently switches to become dependent on protein kinase C epsilon (PKCε). In this study we tested the hypothesis that the delayed onset, PKCε-mediated, component of PGE2 hyperalgesia is generated by the active release of a nucleotide from the peripheral terminal of the primed nociceptor and this nucleotide is then metabolized to produce adenosine, which acts on a Gi-coupled A1 adenosine receptor on the nociceptor to generate PKCε-dependent hyperalgesia. We report that inhibitors of ATP-binding cassette transporters, of ecto-5'-phosphodiesterase and ecto-5'nucleotidase (enzymes involved in the metabolism of cyclic nucleotides to adenosine) and of A1 adenosine receptors each eliminated the late, but not the early, phase of PGE2 -induced hyperalgesia in primed animals. A second model of chronic pain induced by transient attenuation of G-protein-coupled receptor kinase2, in which the prolongation of PGE2 hyperalgesia is not PKCε-dependent, was not attenuated by inhibitors of any of these mechanisms. Based on these results we propose a contribution of an autocrine mechanism, in the peripheral terminal of the nociceptor, in the hyperalgesic priming model of chronic pain.

The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders

A sensory role for ATP was proposed long before general acceptance of its extracellular role. ATP activates and sensitizes signal transmission at multiple sites along the sensory axis, across multiple synapses. P2X and P2Y receptors mediate ATP modulation of sensory pathways and participate in dysregulation, where ATP action directly on primary afferent neurons (PANs), linking receptive field to CNS, has received much attention. Many PANs, especially C-fibers, are activated by ATP, via P2X3-containing trimers. P2X3 knock-out mice and knock-down in rats led to reduced nocifensive activity and visceral reflexes, suggesting that antagonism may offer benefit in sensory disorders. Recently, drug-like P2X3 antagonists, active in a many inflammatory and visceral pain models, have emerged. Significantly, these compounds have no overt CNS action and are inactive versus acute nociception. Selectively targeting ATP sensitization of PANs may lead to therapies that block inappropriate chronic signals at their source, decreasing drivers of peripheral and central wind-up, yet leaving defensive nociceptive and brain functions unperturbed. This article reviews this evidence, focusing on how ATP sensitization of PANs in visceral “hollow” organs primes them to chronic discomfort, irritation and pain (symptoms) as well as exacerbated autonomic reflexes (signs), and how the use of isolated organ-nerve preparations has revealed this mechanism. Urinary and airways systems share many features: dependence on continuous afferent traffic to brainstem centers to coordinate efferent autonomic outflow; loss of descending inhibitory influence in functional and sensory disorders; dependence on ATP in mediating sensory responses to diverse mechanical and chemical stimuli; a mechanistically overlapping array of existing medicines for pathological conditions. These similarities may also play out in terms of future treatment of signs and symptoms, in the potential for benefit of P2X3 antagonists.

Innovative Approaches for the Complexity of Fibromyalgia

Copyright: © 2013 Lawson K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Fibromyalgia (FM) is a chronic condition that presents with a complex of symptoms that include widespread pain, fatigue, dysfunctional sleep and cognitive disruption [1]. The prevalence of this condition is reported to be 2-4% of the population in developed countries, increasing to greater than 7% of those over 70 years of age. As a consequence this presents as a major financial and social burden to patients with FM, their families and carers, and to healthcare systems. FM was classified by the American College of Rheumatology (ACR) in 1990 as widespread pain for at least 3 months and tenderness in at least 11 of 18 defined tender points [2]. The ACR criteria recognise patients with severe pain symptoms, but fail to assess the other symptoms and fulfilment for diagnosis has been suggested to miss 46% of patients with FM [3]. The subjective nature of the tender-point requirement has therefore led to its omission in the current 2010 ACR diagnostic criteria [4]. Significant progress in the understanding of the pathophysiology and identification of effective treatments of FM has been made recently [1,5]. FM is described as a condition of heightened generalized sensitization to sensory input presenting as a complex of symptoms, including pain, where the pathophysiology could include dysfunction of the CNS pain modulatory systems, dysfunction of the neuroendocrine system, and dysautonomia [1,5]. A primary pathophysiological mechanism involves excessive nociceptive neurotransmitter function in the ascending pain signaling pathway in the central nervous system accompanied by a dysfunction in the descending modulatory pathway between the brain and the dorsal horn of the spinal [5].