Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study.

INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation. METHODS: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM). RESULTS: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not. CONCLUSION: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

Conditioned pain modulation-A comprehensive review.

Conditioned pain modulation (CPM) is a centrally processed measure of the net effect of the descending pain pathway. This comprises both the facilitatory as well as the inhibitory effect. In the past, CPM or similar effects have been previously described using different terminologies such as diffuse noxious inhibitory control (DNIC), heterotopic noxious conditioning stimulation (HNCS) or endogenous analgesia (EA). A variety of patient-related factors such as age, gender, hormones, race, genetic and psychological factors have been thought to influence the CPM paradigms. CPM paradigms have also been associated with a wide range of methodological variables including the mode of application of the 'test' as well as the 'conditioning' stimuli. Despite all these variabilities, CPM seems to reliably lend itself to the pain modulation profile concept and could in future become one of the phenotypic biomarkers for pain and also a guide for mechanism-based treatment in chronic pain. Future research should focus on establishing consistent methodologies for measuring CPM and thereby enhancing the robustness of this emerging biomarker for pain.

Changes in peripheral and central sensitization in patients undergoing occipital nerve stimulation.

INTRODUCTION: Central sensitization and impaired conditioned pain modulation (CPM) response have been reported to contribute to migraine progression. Migraine patients can present with allodynia possibly attributed to increased sensitivity of peripheral ends of nociceptors with both peripheral and central sensitization. Occipital nerve stimulation (ONS) works by stimulating the distal branches of C1, C2 and C3 possibly altering the nociceptive traffic to the trigemino-cervical complex, brainstem and supranuclear connections. AIMS: This observational study explores peripheral and central sensitization in patients undergoing percutaneous ONS. METHODS: Following local regulatory approval, 13 patients undergoing ONS with dual Octrode 90 cm leads and rechargeable implantable pulse generator (IPG) (St Jude) were recruited to have quantitative sensory testing (QST) pre- and post-procedure 2 weeks, 1, 3, 6 and 12 months. RESULTS: Patients with intractable migraine demonstrated impaired CPM (mean baseline pressure pain thresholds (PPTs): 61.98 kPa vs 48.01 kPa cuff inflated) prior to ONS, reverting to an efficient CPM response within 2 weeks following ONS implant (68.9 kPa vs 104.5 kPa cuff inflated) and continuing positively over the next 12 months. In contrast, no statistical difference was observed in PPTs. CONCLUSION: This is the first reported observation highlighting the effects on central sensitization following ONS. A consistent and sustained improvement in CPM was observed in contrast to PPT's where there was no difference. Normalisation of the CPM response following ONS indicates that the treatment may reduce central sensitization in the migraine population.

Peripheral nerve stimulation registry for intractable migraine headache (RELIEF): a real-life perspective on the utility of occipital nerve stimulation for chronic migraine.

BACKGROUND: Migraine is common and ranked as the first cause of disability in people under fifty. Despite significant advances in its pharmacological treatment, it often remains intractable. Neuromodulation is one option considered in the management of those patients. OBJECTIVE: To assess the safety and efficacy of neuromodulation in the treatment of intractable chronic migraine using the Abbott occipital nerve stimulator. METHODS: Recruitment took place in 18 centres in 6 countries. Patients over the age of 18 who had failed three or more preventative drugs, had at least moderate disability based on MIDAS or HIT-6 score and were implanted with an Abbott neurostimulator were included in the study. Patients were followed up for a maximum of 24 months. Data were collected on adverse events, headache relief, headache days, quality of life, migraine disability, satisfaction and quality of life. RESULTS: One hundred twelve patients were included, 79 female and 33 male, with 45 patients reaching the maximum follow-up of 24 months. At 3 months, 33.7% were satisfied or very satisfied with the procedure with 43.0% reporting improved or greatly improved quality of life. 67.5% indicated that they would undergo the procedure again with satisfaction peaking at 9 months when 49.3% were satisfied or very satisfied with the procedure. At 24 months, 46.7% of available patients were satisfied or very satisfied with the procedure-18% of enrolled patients. The adverse events were however frequent with incidences of 37%, 47% and 31% respectively for hardware-, biological and stimulation-related side effects. CONCLUSION: Neuromodulation can be beneficial for selected patients with intractable chronic migraine although frequent complications have been consistently reported across studies. Further research focusing on development of better hardware and technique optimisation and in particular reliable randomised trials with significantly longer follow-ups are warranted in this field.

Metabolic Imaging of Pain Matrix Using 18 F Fluoro-deoxyglucose Positron Emission Tomography/Computed Tomography for Patients Undergoing L2 Dorsal Root Ganglion Stimulation for Low Back Pain.

INTRODUCTION: Nociceptive signals from lumbar intervertebral discs ascend in the sympathetic chain via the L2 dorsal root ganglion (L2 DRG), a potential target for discogenic low back pain in neuromodulation. Positron Emission Tomography/Computed Tomography (PET-CT) measures functional changes in the brain metabolic activity, identified by the changes in the regional cerebral blood flow (rCBF) as determined by the changes of F-18 Fluoro-deoxyglucose (18 F FDG) tracer within brain tissues. METHODS AND MATERIALS: Nine patients were recruited to explore the changes in PET-CT imaging at baseline and four-weeks post implantation of bilateral L2 DRG neurostimulation leads and implantable pulse generator (IPG). PET-CT scans were performed 30 min following an IV injection of 250±10% MBq of 18 F FDG tracer. Fifteen frames were acquired in 15 min. PET list-mode raw data were reconstructed and normalized appropriately to a brain anatomical atlas. RESULTS: Nine patients were recruited to the study, where PET-CT imaging data for five patients were analyzed. The right and left insular cortex, primary and secondary somato-sensory cortices, prefrontal cortex, anterior cingulate cortex, thalamus, amygdala, hippocampus and the midline periaqueductal areas, were assessed for any changes in the metabolic activity. A total of 85 pain matrix regions were delineated SUV (standardized uptake value)MAX , SUV MEAN ± SD, and SUVPEAK were calculated for each of these regions of the brain and were compared pre- and post-L2 DRG stimulation. Sixty-one of the 85 matrices showed an increase in metabolic activity whereas 24 matrices showed a reduction in metabolic activity. CONCLUSION: This is the first ever study reporting the changes in cerebral metabolic activity and multi-frame static brain 18 F FDG PET imaging after L2 DRG stimulation for discogenic low back pain. Predominantly an increased metabolic activity in nociceptive brain matrices are seen with an increased in F18 F FDG uptake following L2 DRG stimulation.

A randomized pilot study to investigate the effect of opioids on immunomarkers using gene expression profiling during surgery.

Endogenous opioid peptides and exogenous opioids modulate immune function, and animal and human studies have shown that some have a depressant immunomodulatory effect. This is potentially of high clinical significance, eg, in cancer patients and surgery. The primary objective of this pilot study was to evaluate the effect of morphine and oxycodone on immune pathways associated with immunosuppression in gynecological laparotomy patients. Gene expression was analyzed in CD4, CD8, and natural killer (NK) cells using the 3' Affymetrix microarray. Patients were randomized to receive morphine, oxycodone, or nonopioid "control" analgesia during and after surgery. Genes demonstrating differential expression were those with a ≥±2-fold difference and P-value ≤0.05 after analysis of variance. Cytometric bead array and NK cell degranulation assay were used to investigate changes in serum cytokine concentration and in NK cell cytotoxicity, respectively. Forty patients had satisfactory RNA which was hybridized to gene chips. Genes were identified (Partek Genomics Suite 6.6) at baseline, 2, 6, and 24 hours and were either ≥2-fold upregulated or downregulated from baseline. At 2 hours, a large number of genes were downregulated with morphine but not with control analgesia or oxycodone. Statistically significant increases in IL-6 concentrations were induced by morphine only; NK cell activity was suppressed with morphine, but maintained with oxycodone and epidural analgesia. Gene expression profiles suggest that at 2 hours, post incision morphine appeared to be immunosuppressive as compared to oxycodone and nonopioid control analgesia.

Characterizing the Somatosensory Profile of Patients With Failed Back Surgery Syndrome With Unilateral Lumbar Radiculopathy Undergoing Spinal Cord Stimulation: A Single Center Prospective Pilot Study.

OBJECTIVES: Currently little objective evidence exists regarding the phenotype or somato-sensory profile of patients with Failed Back Surgery Syndrome (FBSS). The aim of this study is to characterize the somato-sensory profile of the patients with FBSS undergoing spinal cord stimulation (SCS). METHODS: A combined quantitative sensory test and questionnaire approach was used to characterize the somatosensory profiles of patients undergoing SCS. RESULTS: Baseline somatosensory profiles were obtained from 23 patients and full three-month data was obtained from 19 patients. At baseline, there was a high prevalence (>50% prevalence of moderate to severe sensation) of burning, tingling, electric shock, numbness, and pressure pain sensitivity. None of the sensory symptoms were present at significant levels at three months following SCS. At baseline, 65% of patients had an inefficient conditioned pain modulation (CPM). Three months post-SCS, 95% of patients had an efficient CPM. All the patients who had an inefficient CPM at baseline had a successful implant at three months and their CPM became efficient in all but one patient. Only 50% of the patients with an efficient CPM at baseline, had a successful implant at three months post-SCS. CONCLUSION: Although very low numbers, we could demonstrate the somatosensory profiles of patients with FBSS undergoing SCS. Early indication may associate an efficient CPM profile having a higher chance of an unsuccessful implant at three months.

A pilot study investigating whether quantitative sensory testing alters after treatment in patients with fibromyalgia.

BACKGROUND: Fibromyalgia is a chronic musculoskeletal pain condition that is often associated with sleep disturbances and fatigue. The pathophysiology of fibromyalgia is not understood, but indirect evidence suggests a central dysfunction of the nociceptive modulating system. The aim of this study was to evaluate whether quantitative sensory testing detects a change in pain thresholds in fibromyalgia patient receiving pregabalin treatment. METHODS: A total of 25 patients were recruited for the study and received routine pregabalin, but only 14 patients completed the treatment. Assessment of pressure pain thresholds and changes in conditioned pain modulation using ischaemic pain as a conditioning stimulus were measured at baseline and every 4 weeks for 12 weeks. Fibromyalgia impact questionnaire, PainDETECT and SF-12 were also completed. RESULTS: Patients with fibromyalgia demonstrated a less-efficient conditioned pain modulation at baseline. An efficient conditioned pain modulation was observed at 1 month and this was maintained until the final visit. Pressure pain thresholds (PPTs) showed a significant improvement from baseline. Patients also reported a similar magnitude of improvements in PainDETECT, fibromyalgia impact questionnaire (FIQ) and its impact on daily life and change in outcome for SF-12. CONCLUSION: This pilot study reports an increase in PPTs and improved conditioned pain modulation response after commencing pregabalin, which was maintained at 12 weeks, and this was supported by positive pain scores. Pregabalin is a licenced treatment for fibromyalgia in Europe, and its response to central sensitisation, particularly 'dynamic responses', has not been reported. We conclude that pregabalin has the potential to reduce peripheral and central sensitisation in patients with fibromyalgia, as measured using quantitative sensory testing.

Detection of CFTR transgene mRNA expression in respiratory epithelium isolated from the murine nasal cavity.

BACKGROUND: When assessing the efficacy of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy, we routinely evaluate gene transfer in the mouse nose and measure transfection efficiency by assessing transgene-specific mRNA using the real-time (TaqMan) quantitative reverse transcriptase-polymerase chain reaction. TaqMan is traditionally used to quantify expression in whole tissue homogenates, which in the nose would contain many cells types, including respiratory and olfactory epithelium. Only the respiratory epithelium is a satisfactory model for human airway epithelium and therefore CFTR gene transfer should be specifically assessed in respiratory epithelial cells (RECs). METHODS: We have compared laser microdissection, pronase digestion and nasal brushing for: (i) the ability to enrich RECs from the wild-type mouse nose and (ii) the length of time to perform the procedure. Using TaqMan, we subsequently assessed gene transfer in enriched RECs after nasal perfusion of GL67A/pCF1-CFTR complexes in a CF mouse model. RESULTS: Laser microdissection successfully isolated RECs; however, time-consuming sample preparation made this technique unsuitable for high-throughput studies. Pronase digestion was sufficiently rapid but only yielded 19% (range = 13%) RECs (n = 6). The nasal brushing method was superior, yielding 92% (range = 15%) RECs (n = 8) and was equally effective in CF knockout mice (91%, range = 14%, n = 10). Importantly, gene transfer was detectable in brushed RECs from 70% of perfused mice and the number of vector-specific transcripts was comparable to 3.5% of endogenous wild-type Cftr levels. CONCLUSIONS: Isolation of RECs by brushing allows accurate assessment of GTA transfection efficiency in an experimental system that is relevant for CF gene therapy.

Limitations of the murine nose in the development of nonviral airway gene transfer.

A clinical program to assess whether lipid GL67A-mediated gene transfer can ameliorate cystic fibrosis (CF) lung disease is currently being undertaken by the UK CF Gene Therapy Consortium. We have evaluated GL67A gene transfer to the murine nasal epithelium of wild-type and CF knockout mice to assess this tissue as a test site for gene transfer agents. The plasmids used were regulated by either (1) the commonly used short-acting cytomegalovirus promoter/enhancer or (2) the ubiquitin C promoter. In a study of approximately 400 mice with CF, vector-specific CF transmembrane conductance regulator (CFTR) mRNA was detected in nasal epithelial cells of 82% of mice treated with a cytomegalovirus-plasmid (pCF1-CFTR), and 62% of mice treated with an ubiquitin C-plasmid. We then assessed whether CFTR gene transfer corrected a panel of CFTR-specific endpoint assays in the murine nose, including ion transport, periciliary liquid height, and ex vivo bacterial adherence. Importantly, even with the comparatively large number of animals assessed, the CFTR function studies were only powered to detect changes of more than 50% toward wild-type values. Within this limitation, no significant correction of the CF phenotype was detected. At the current levels of gene transfer efficiency achievable with nonviral vectors, the murine nose is of limited value as a stepping stone to human trials.

Arthritis and pain. Current approaches in the treatment of arthritic pain.

Current evidence suggests that although persistent arthritic pain is initiated and maintained by articular pathology, it is also heavily influenced by a range of other factors. Strategies for treating arthritic pain are therefore different from those adopted for acute pain. Although published guidelines offer general assistance, the complexity of underlying mechanisms requires that measures designed to relieve pain must take into account individual biological, psychological and societal factors. It follows that a combination of both pharmacological and non-pharmacological approaches offers the best opportunity for therapeutic success, although determining the effectiveness of such complex interventions remains difficult. Pharmacological therapy is often prolonged, and safety and tolerability issues become as important as efficacy over time.