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BACKGROUND: Central neuropathic pain (CNP), pain initiated or caused by a primary lesion or dysfunction of the central nervous system, occurs in 28% of patients with multiple sclerosis (MS). Delta(9)-Tetrahydrocannabinol/cannabidiol (THC/CBD), an endocannabinoid system modulator, has demonstrated efficacy for up to 4 weeks in randomized controlled trials in the treatment of CNP in patients with MS. OBJECTIVE: The purpose of this extension was to establish long-term tolerability and effectiveness profiles for THC/CBD (Sativex (R), GW Pharmaceuticals plc, Salisbury, United Kingdom) oromucosal spray in CNP associated with MS. METHODS: This uncontrolled, open-label trial was an indefinite-duration extension of a previously reported 5-week randomized study in patients with MS and CNP. In the initial trial, patients were randomized to placebo or THC/CBD. Patients were only required to maintain their existing analgesia in the randomized study. In the open-label trial they could vary their other analgesia as required. All patients (placebo and THC/CBD) who completed the randomized trial commenced the open-label follow-up on THC/CBD (27 mg/mL: 25 mg/mL). Patients titrated their dosage, maintaining their existing analgesia. The primary end point of the trial was the number, frequency, and type of adverse events (AEs) reported by patients. Secondary end points included changes from baseline in 11-point numerical rating scale (NRS-11) neuropathic pain score, hematology and clinical chemistry test results, vital signs, trial drug usage, and intoxication visual analogue scale scores. RESULTS: Sixty-six patients were enrolled in the randomized trial; 64 (97%) completed the randomized trial and 63 (95%) entered the open-label extension (race, white, 100%; sex, male, 14 [22%]; mean [SD] age, 49 [8.4] years [range, 27-71 years[). The mean (SD) duration of open-label treatment was 463 (378) days (median, 638 days; range, 3-917 days), with 34 (54%) patients completing >1 year of treatment with THC/CBD and 28 (44%) patients completing the open-label trial with a mean (SD) duration of treatment of 839 (42) days (median, 845 days; range, 701-917 days). Mean NRS-11 pain scores in the final week of the randomized trial were 3.8 in the treatment group and 5.0 in the placebo group. In the 28 (44%) patients who completed the 2-year follow up, the mean (SD) NRS-11 pain score in the final week of treatment was 2.9 (2.0) (range, 0-8.0). Fifty-eight (92%) patients experienced > or =1 treatment-related AE. These AEs were rated by the investigator as mild in 47 (75%) patients, moderate in 49 (78%), and severe in 32 (51%). The most commonly reported AEs were dizziness (27%), nausea (18 %), and feeling intoxicated (11%). Two treatment-related serious AEs (ventricular bigeminy and circulatory collapse) were judged to be treatment-related. Both serious AEs occurred in the same patient and resolved completely following a period of discontinuation. Eleven (17%) patients experienced oral discomfort, 4 persistently. Regular oral examinations revealed that 7 (11%) patients developed white buccal mucosal patches and 2 (3%) developed red buccal mucosal patches; all cases were deemed mild and resolved. Seventeen (25%) patients withdrew due to AEs. The mean number of sprays and patients experiencing intoxication remained stable throughout the follow-up trial. CONCLUSIONS: THC/CBD was effective, with no evidence of tolerance, in these select patients with CNP and MS who completed approximately 2 years of treatment (n = 28). Ninety-two percent of patients experienced an AE, the most common of which were dizziness and nausea. The majority of AEs were deemed to be of mild to moderate severity by the investigators. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pain is a personal experience influenced by multiple biopsychosocial factors. Using a pain intensity measure alone to assess the effectiveness of a chronic pain intervention fails to fully evaluate its impact on the multifaceted chronic pain experience. The holistic minimal clinically important difference (MCID) is a composite outcome developed to provide a comprehensive assessment of chronic pain in response to intervention, across 5 outcome domains: pain intensity, health-related quality of life, sleep quality, physical, and emotional function. To focus on domains where the individual need is greatest, the holistic MCID reflects the cumulative MCID averaged over only the domains where subjects were impaired preintervention., Objectives: To assess the internal and construct validity of the Holistic MCID score to inform its future use as an evidence-based tool., Methods: This validation study was undertaken using data from the EVOKE trial with 111 patients up to 24-month follow-up. Internal consistency of the holistic MCID was assessed using Cronbach alpha statistic and dimensional exploration using principal component analysis., Results: The holistic MCID measure demonstrated strong internal consistency with Cronbach alpha >0.7 at all follow-ups. Principal component analysis showed one overarching holistic dimension to be present in the composite. Construct validity was demonstrated by an increase in the holistic MCID score being associated with both increased Patients' Global Impression of Change, EuroQol visual analogue scale score, and each of the outcome domains in a "leave-one-out" analysis (all P < 0.001)., Conclusion: The holistic MCID provides a valid measure for the comprehensive, personalized assessment of response after a chronic pain intervention. The validity of the holistic MCID requires further confirmation in other chronic pain populations and with different interventions., Competing Interests: R.S.T. reports consultancy fees from Medtronic, Nevro and Saluda Medical outside the submitted work. C.M.M. is employed by NAMSA, a company that provides consulting and testing services to medical device manufacturers. N.A.M. reports receiving grants from Neuros, Mesoblast, and Vivex Biologics, as well as consulting as a medical monitor for Saluda Medical, Nevro, Vivex Biologics, Mainstay, Sollis Therapeutics, and Vertos outside the submitted work. J.W.K. is an advisory board member for Boston Scientific, Medtronic, Abbott, and Saluda Medical. J.E.P. reports research and consulting fees from Saluda Medical during the conduct of the study; consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from: Abbott, Flowonix, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a shareholder of Vertos, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. C.W.H. has received consultancy fees from Saluda Medical and Genecentrix outside the submitted work. S.J.C. reports receiving grants from Saluda Medical, Vertos, Mainstay, and Vivex outside the submitted work. L.K. reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical outside the submitted work. C.A.G. reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific and Saluda Medical outside the submitted work. E.A.P. has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda Medical outside the submitted work, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos outside the submitted work. She holds stock options from SynerFuse and neuro42. K.V.P. is a consultant and speaker for Abbott. S.E. reports consultancy fees from Medtronic, and Mainstay Medical outside the submitted work. He has received department research funding from the National Institute of Health Research, Saluda Medical and Medtronic. R.M.L. is an uncompensated consultant for Biotronik, Abbott, Nalu, Saluda Medical, and Mainstay Medical and has stock options from Nalu and Saluda Medical. C.G. reports payment to his institution (for part of his salary) and stock options received from Mainstay, personal fees from Mainstay, Saluda Medical, Persica, and Iliad outside the submitted work, research funded by Sollis, expert witness testimony fees, and serves as Editor-in-Chief of Pain Practice. S.D. has received consulting payments from Averitas Pharma and Biotronik outside the submitted work. A.A. reports consultancy for Medtronic, Avanos, and StimWave outside the submitted work. P.B. reports consulting fees from Abbott and PainTEQ outside the submitted work. E.H., A.L., N.S. and R.V.D. are employees of Saluda Medical. R.V.D. has previously received consultancy fees from Mainstay Medical, Medtronic, and Saluda Medical. D.J.C. has consulted for AbbVie, Heron Therapeutics, Aptinyx, Neumentum, Regeneron Pharmaceuticals, Swing Therapeutics, Virios Therapeutics, Allergan Sales, Eli Lilly and Company, H. Lundback A/S, Pfizer, Samumed, Tonix Pharmaceuticals. T.J.N. has received consultancy fees from Saluda Medical outside the submitted work. The remaining authors declare no conflict of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Dynamic Mechanical Allodynia (DMA) is a typical symptom of neuropathic pain (NP). In a recent study, the capsaicin 8% patch was noninferior to pregabalin in overall peripheral NP relief. In this study, we report the comparison of the two treatments in relieving DMA., Methods: In a randomized, open-label, head-to-head, 8-week study, 488 patients with peripheral NP were treated with the capsaicin 8% patch (one application) or an optimized dose of pregabalin. Assessments included the area and intensity of DMA, and the number of patients achieving complete resolution of DMA., Results: At baseline, 253 patients in the capsaicin 8% patch group and 235 patients in the pregabalin group had DMA. From baseline to end of study, the change in DMA intensity was significantly in favour of the capsaicin 8% patch versus pregabalin [-0.63 (95% CI: -1.04, -0.23; p = 0.002)]. Similarly, the capsaicin 8% patch was superior to pregabalin in reducing the area of DMA [-39.5 cm 2 (95% CI: -69.1, -10.0; p = 0.009)] from baseline to end of study. Overall, a greater proportion of patients had a complete resolution of allodynia with capsaicin 8% patch treatment compared with pregabalin treatment (24.1% vs. 12.3%; p = 0.001) at end of study., Conclusion: Capsaicin 8% treatment was superior to pregabalin in reducing the intensity and area of DMA, and in the number of patients with complete resolution of DMA., Significance: The superiority of a topical treatment over pregabalin in relieving DMA supports the view that both peripheral and central sensitization can mediate allodynia., (© 2017 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Objectives: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain., Methods: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5)., Results: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12., Conclusions: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

Background: Clinical trials have not yet compared the efficacy of capsaicin 8% patch with current standard therapy in peripheral neuropathic pain (PNP)., Objectives: Head-to-head efficacy and safety trial comparing the capsaicin patch with pregabalin in PNP., Methods: Open-label, randomized, multicentre, non-inferiority trial. Patients with PNP, aged 18-80 years, were randomly assigned to either the capsaicin 8% patch (n = 282) or an optimised dose of oral pregabalin (n = 277), and assessed for a ≥30% mean decrease in Numeric Pain Rating Scale (NPRS) score from baseline to Week 8. Secondary endpoints included optimal therapeutic effect (OTE), time-to-onset of pain relief and treatment satisfaction., Results: The capsaicin 8% patch was non-inferior to pregabalin in achievement of a ≥30% mean decrease in NPRS score from baseline to Week 8 (55.7% vs. 54.5%, respectively; Odds ratio: 1.03 [95% CI: 0.72, 1.50]). The proportion of patients achieving OTE at Week 8 was 52.1% for the capsaicin 8% patch versus 44.8% for pregabalin (difference: 7.3%; 95% CI: -0.9%, 15.6%). The median time-to-onset of pain relief was significantly shorter for capsaicin 8% patch versus pregabalin (7.5 vs. 36.0 days; Hazard ratio: 1.68 [95% CI: 1.35, 2.08]; p < 0.0001). Treatment satisfaction was also significantly greater with the capsaicin 8% patch versus pregabalin. TEAEs were mild-to-moderate in severity, and resulted in treatment discontinuation only with pregabalin (n = 24). Systemic adverse drug reactions ranged from 0 to 1.1% with capsaicin 8% patch and 2.5 to 18.4% with pregabalin., Conclusions: The capsaicin 8% patch provided non-inferior pain relief to an optimized dose of pregabalin in PNP, with a faster onset of action, fewer systemic side effects and greater treatment satisfaction., (© 2015 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

Unlabelled: The typical placebo response (ie, the nonspecific effects in the placebo group including benign natural course, regression to the mean, expectation/conditioning effects, and others) in randomized trials in complex regional pain syndrome (CRPS) is unknown. We recently observed a surprising near-absence of placebo response in a randomized controlled trial we conducted on patients with long-standing (≥6 months) CRPS. To investigate the idea that there may be an absence of placebo response in long-standing CRPS further, we conducted a systematic review and meta-analysis of placebo responses in randomized controlled trials conducted in patients with CRPS of ≥6 months. We systematically identified suitable randomized controlled trials published between 1966 and September 2013. We calculated the mean difference and standard error of the mean difference for placebo responses and synthesized individual effect sizes at 4 specified time periods of interest (15-30 minutes, 1 week, 3-4 weeks, and 6 weeks or more) via meta-analysis using the method of inverse-variance. Heterogeneity was assessed according to the I(2) statistic. For primary analysis, we pooled trial-specific effect sizes over the 4 time points. We analyzed data from 340 participants from 18 trials out of a possible 361 participants from 20 trials (94% of participants analyzed). Significant heterogeneity was present between trials; therefore, we interpreted trends from visual inspection of individual trials and pooled estimates. Placebo response was significant at the earliest time period (15-30 minutes). There was no significant evidence of placebo response at any of the other time periods. These results inform the design of future trials, and they caution against the "therapeutic" use of placebo in long-standing CRPS., Perspective: In this meta-analysis of placebo responses in randomized controlled trials in long-standing CRPS, published during 1966 to 2013, we found no evidence for placebo analgesia, except at very early time points. Results inform the design of future placebo analgesia research in long-standing CRPS., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Why only certain patients develop debilitating pain after spinal chord injury and whether structural brain changes are implicated remain unknown. The aim of this study was to determine if patients with chronic, neuropathic below-level pain have specific cerebral changes compared to those who remain pain-free. Voxel-based morphometry of high resolution, T1-weighted images was performed on three subject groups comprising patients with pain (SCI-P, n = 18), patients without pain (SCI-N, n = 12) and age- and sex-matched controls (n = 18). The SCI-P group was first compared directly with the SCI-N group and then subsequently with controls. Overall, grey and white matter changes dependent on the presence of pain were revealed. Significant changes were found within the somatosensory cortex and also in corticospinal tracts and visual-processing areas. When the SCI-P group was directly compared with the SCI-N group, reduced grey matter volume was found in the deafferented leg area of the somatosensory cortex bilaterally. This region negatively correlated with pain intensity. Relative to controls, grey matter in this paracentral primary sensory cortex was decreased in SCI-P but conversely increased in SCI-N. When compared with controls, discrepant corticospinal tract white matter reductions were found in SCI-P and in SCI-N. In the visual cortex, SCI-N showed increased grey matter, whilst the SCI-N showed reduced white matter. In conclusion, structural changes in SCI are related to the presence and degree of below-level pain and involve but are not limited to the sensorimotor cortices. Pain-related structural plasticity may hold clinical implications for the prevention and management of refractory neuropathic pain.

Objective: To evaluate cortical activation patterns during mechanical-tactile stimulation in fibromyalgia syndrome (FMS) patients and to correlate cortical activation changes with clinical symptoms., Methods: Nineteen female FMS patients and 18 matched, healthy control subjects underwent EEG examination during brushing stimulation of the right forearm. Participants rated any pain experienced and underwent a manual tender point scale (MTPS) examination. Amplitude changes of cortical rhythms during brushing were analysed in alpha (8-13 Hz) and beta (16-24 Hz) frequency bands., Results: Thirteen patients reported pain during brushing. Independent t-test comparison of event related desynchronisation (ERD) during brushing revealed a cluster of electrodes over ipsilateral (right) central-parietal region which demonstrated ERD in patients only. Clinical MTPS scores correlated with beta-band ERD in this cluster of electrodes. Beamformer analysis revealed a widespread array of source activations in patients, including bilateral insula and primary and secondary somatosensory cortices. Control subject source activations were limited to contralateral (left) hemisphere., Conclusions: Results indicate ipsilateral cortical activations in FMS patients, but not in healthy controls, during brushing. Ipsilateral ERD during brushing is associated with MTPS score suggesting abnormal processing of somatosensory input which may contribute to clinical pain., Significance: Altered functioning in FMS may reflect physiological changes in response to afferent somatosensory information manifesting in chronic pain., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Repeated warm laser stimuli produce a progressive increase of the sensation of warmth and heat and eventually that of a burning pain. The pain resulting from repetitive warm stimuli is mediated by summated C fibre responses. To shed more light on the cortical changes associated with pain during repeated subnoxious warm stimulation, we analysed magnetoencephalographic (MEG) evoked fields in eleven subjects during application of repetitive warm laser stimuli to the dorsum of the right hand. One set of stimuli encompassed 10 laser pulses occurring at 2.5 s intervals. Parameters of laser stimulation were optimised to elicit a pleasant warm sensation upon a single stimulus with a rise of skin temperature after repeated stimulation not exceeding the threshold of C mechano-heat fibres. Subjects reported a progressive increase of the intensity of heat and burning pain during repeated laser stimulation in spite of only mild (4.8°C) increase of skin temperature from the first stimulus to the tenth stimulus. The mean reaction time, evaluated in six subjects, was 1.33 s, confirming involvement of C fibres. The neuromagnetic fields were modelled by five equivalent source dipoles located in the occipital cortex, cerebellum, posterior cingulate cortex, and left and right operculo-insular cortex. The only component showing statistically significant changes during repetitive laser stimulation was the late component of the contralateral operculo-insular source peaking at 1.05 s after stimulus onset. The amplitude increases of the late component of the contralateral operculo-insular source dipole correlated with the subjects' numerical ratings of warmth and pain. Results point to a pivotal role of the contralateral operculo-insular region in processing of C-fibre mediated pain during repeated subnoxious laser stimulation.

Central neuropathic pain is common in multiple sclerosis (MS), and its prevalence increases with physical disability. Sufficient evidence links dysesthetic pain, trigeminal neuralgia, Lhermitte's sign, and painful tonics spasms to plaque formation in the spinal cord and brain, whereas the association with headache and back pain remains unclear. Management varies according to the pain in question. For dysesthetic pain, drugs in use for neuropathic pain in general are recommended as first-line treatment, and emerging evidence suggests some benefit from cannabinoids and levetiracetam. Because of unique characteristics of MS-related trigeminal neuralgia, ganglion and root level neuroablative procedures are worth considering before microvascular decompression. Overall, the lack of controlled clinical trials, together with our limited understanding of the pathophysiological mechanisms involved, form a hindrance to a systematic and rational management of MS-related pain.

Objective: Evaluation of the effectiveness of Microvascular Decompression (MVD) for Trigeminal Neuralgia (TGN), with emphasis on patient's perception of outcome, and satisfaction with the procedure., Materials and Methods: A cohort of 372 MVD operations carried out between 1982 and 2005 were reviewed, contact could be attempted with 319 patients. Questionnaires assessing the patient's perception of outcome returned by 266 patients (71%). statistical analysis of the data was carried out using a cox proportional-hazard regression analysis. Anticipated outcome measures: Time to pain recurrence; predictive value of imaging, operative findings and complications; patients' satisfaction, and outcome of revision MVD., Results: Complete pain relief (off medication) achieved in 71% of patients at 10 years. Overall 84% of responders to questionnaires expressed satisfaction with the operative outcome, the mean duration of TGN was 80 months and mean post-operative follow-up of 7 years. No mortality reported in this series., Conclusion: This is a large review of MVD, which confirms the long-term effectiveness of the procedure, and uniquely reflects patient's perception of the operation. Predictors of favourable outcome were shorter preoperative duration of TGN, older age at time of MVD, typical features, and vascular compression; moreover, complications, and previous neurodestructive procedures did not show significant effect on long-term pain relief. Satisfaction with MVD was exclusively related to long-term pain relief without medications.

Trigeminal neuralgia is a common cause of facial pain. It has a significant impact on the quality of life and the socioeconomic functioning of the patient. The aim of this review is to provide recommendations for medical management of trigeminal neuralgia based on current evidence. Based upon the analyses of the literature combined with experience in pain management, symptoms, assessment, differential diagnosis, and treatment possibilities of trigeminal neuralgia are described and discussed. Recommendations for pain management are given and are displayed in a clinical practice algorithm. Treatment should be multidisciplinary. Various treatment options and their risks should be discussed with the patient. The first treatment of choice is carbamazepine or oxcarbazepine. In younger patients, the first choice of invasive treatment is probably microvascular decompression. For elderly patients, radiofrequency treatment of Gasserian ganglion is recommended and the technique is described in detail.

Neuropathic pain is frequently associated with negative effects on quality of life (QoL), affecting physical, social, and psychological functioning. Of many existing scales used to measure QoL, none have been validated in a neuropathic pain patient population. This study reports on the development and preliminary psychometric evaluation of the Neuropathic Pain Impact on Quality-of-Life questionnaire (NePIQoL), a measure to assess QoL in neuropathic pain. In Phase I, focus groups with 27 patients and a panel of experts identified QoL issues for inclusion in the measure. Initial items (152) and response categories were pretested using cognitive interviewing (18 patients). Following this, the number of items was reduced to 91. In Phase II, the 91-item version of the NePIQoL was administered to a further 112 patients, poorly performing items were identified, and internal consistency was examined. In Phase III, the revised NePIQoL was administered to a further 110 patients on two occasions to examine validity and test-retest reliability. Qualitative and quantitative pretesting led to extensive revision, resulting in a final measure of 42 items. Finally, Phase IV tested the concurrent validity and responsiveness of the NePIQoL. The authors conclude that the NePIQoL is an acceptable, patient-derived, neuropathic pain-specific measure with evidence of reliability, validity, and temporal stability.

In diabetic patients small fiber neuropathy has been associated with impairment of 0.1 Hz microvascular vasomotion. The aim of this study was (1) to investigate whether vasoconstriction-induced microvascular oscillations in the skin are reduced in diabetic patients with peripheral and/or autonomic neuropathy, and (2) whether this method could be used as a non-invasive surrogate marker to assess diabetic small fiber neuropathy. Four matched groups were studied: diabetic patients without neuropathy (D), with peripheral neuropathy (DPN), with peripheral and autonomic neuropathy (DAN), and non-diabetic controls (Ctrl). All participants were evaluated for peripheral and autonomic neuropathy, microvascular endothelial function, and metabolic syndrome indicators. Laser Doppler flowmetry was used to measure oscillations after iontophoresis of the alpha one selective agonist phenylephrine. approximately 0.1-Hz oscillations recorded at the foot were significantly attenuated in diabetic patients with peripheral and/or autonomic neuropathy (DPN and DAN groups) compared to diabetic patients without neuropathy or non-diabetic controls. In the forearm, microvascular oscillations were significantly reduced only in patients with autonomic neuropathy (DAN). Oscillation measures correlated significantly (P<0.001) with all markers of peripheral neuropathy but not with markers of measurements of microvascular endothelial function, or metabolic syndrome markers. In a logistic regression model, reduced microvascular oscillations at the foot were a strong predictor for the presence of peripheral neuropathy. The measurement of phenylephrine-induced approxiamtely 0.1-Hz microvascular oscillation may represent a useful non-invasive tool with which to study the effects of treatment strategies on the diabetic small fiber neuropathy.

Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.

Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

Background: Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN., Methods and Findings: We systematically searched databases (MEDLINE 1966-2004, EMBASE 1988-2004, CINAHL 1982-2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat. Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25. This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, "strong" opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated. Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as "not yet adequately tested" rather than demonstrating "no evidence of efficacy." Topical aspirin/diethyl ether has not been adequately tested., Conclusion: The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.

Postherpetic neuralgia (PHN) remains one of the most troublesome common chronic neuropathic pain conditions. Many controlled trials have been published showing good efficacy and reasonable tolerability. These include gabapentinoids, opioids, tricyclic antidepressants, and topical lidocaine and capsaicin. Combination therapies are possible, but have not been proven, and long-term follow-up is limited. Only few case series exist for surgical and other invasive therapies and their role remains uncertain.

Aims: A cross-sectional study has been performed in order to estimate the prevalence, severity, and current treatment of chronic painful peripheral neuropathy (CPPN) in people with diabetes in the community., Methods: Using a structured questionnaire and examination we have assessed these factors in a community sample of people with diabetes (n=350) and compared them with 344 age- and sex-matched people without diabetes from the same locality., Results: The prevalence of CPPN was estimated to be 16.2%[95% confidence interval (CI): 6.8-16%] in people with diabetes compared with 4.9% (95% CI: 2.6-7.2%) in the control sample (P < 0.0001). Diabetic subjects with and without CPPN did not differ in age, sex, type and duration of diabetes, body mass index, smoking status and glycaemic control. However, CPPN diabetic subjects had significantly higher Visual Analogue Scale (VAS) scores for pain over the preceding 24 h [median (interquartile range) 3.5 (1.5-6.7) cm vs. 0.7 (0-3.9) cm, P < 0.0001]. Also, the total McGill Pain Questionnaire Score (a measure of pain quality and severity) was 18 (13-31.5) vs. 10 (4-16) (P < 0.0001). Of patients with diabetes and CPPN, 12.5% (7/56) had never reported their symptoms to their treating physician and 39.3% (22/56) had never received any treatment for their painful symptoms., Conclusions: CPPN is common, often severe but frequently unreported and inadequately treated.

Brain activity was studied by fMRI in 18 healthy subjects during stimulation of the thenar eminence of the hand with either warm (non-painful, 40 degrees C) or hot (painful, 46-49 degrees C) stimuli using a contact thermode. Experiments were performed on the right and left hand independently and with two attentional contexts: subjects either attended to pain or attended to a visual global motion discrimination task (to distract them from pain). Group analysis demonstrated that attended warm stimulation of the right hand did not produce any significantly activated clusters. Painful thermal stimulation of either hand elicited significant activity over a large network of brain regions, including insula, inferior frontal gyrus, cingulate gyrus, secondary somatosensory cortex, cerebellum, and medial frontal gyrus (corrected P < 0.05). Insula activity was distributed along its anterior-posterior axis and depended on the hand stimulated and attentional context. In particular, activity within the posterior insula was contralateral to the site of stimulation, tested using regions of interest (ROI) analysis: significant side x site interaction (P = 0.001). With attention diverted from the painful stimulus bilateral anterior insula activity moved posteriorly to midinsula and decreased in extent (ROI analysis: significant main effect of attention (P = 0.03)). The role of the insula in thermosensation and attention is discussed.

Unlabelled: This review discusses the various peripheral and ganglion-level procedures available for treating trigeminal neuralgia and summarizes specific success and complication rates for each technique., Method: A review of the available literature., Results: It appears that expertly performed ganglion-level procedures (radiofrequency thermocoagulation, balloon compression, and glycerolysis) are more effective than peripheral procedures but neither approach can be relied on to produce long-term pain relief. All of these procedures are neurodestructive and can cause sensory loss and dysesthesia. Effective drug therapy may not be acceptable to some patients as adverse cognitive side effects are increasingly recognized., Conclusions: Each patient should receive an informed and impartial account of the available surgical options. There is a need for prospective randomized controlled studies in procedure-naïve subjects to determine the optimal surgical management of trigeminal neuralgia.

Central pain is common in patients with stroke, multiple sclerosis, syringomyelia, and spinal cord injury. It frequently develops after a delay of weeks or months, is associated with sensory change involving the spinothalamic pathways, and has a poor prognosis for spontaneous remission. Hypotheses to explain the varied clinical manifestations can be divided in two categories: those stressing aberrant neural activity in the deafferented circuits and those focusing on the postlesion imbalance between facilitatory and inhibitory neural pathways. All models inherently assume a degree of specialization of cerebral structures in pain processing, which has not been proved conclusively.

This study was conducted to determine somatosensory perception thresholds in 97 immunocompetent patients with herpes zoster (HZ), and to evaluate their associations with the development of post-herpetic neuralgia (PHN). Warm, cold and heat pain thresholds were tested by Thermotest (SOMEDIC) and tactile thresholds by Semmes-Weinstein monofilaments. To establish reference values, 103 healthy subjects underwent somatosensory testing, from which values were calculated for both genders for four age groups (<60, 60-69, 70-79 and >/=80years) in five dermatomal levels (VI, C3, T3, T10 and S1). Patients with HZ underwent quantitative somatosensory testing within the affected dermatome, its mirror image dermatome and an adjacent dermatome bilaterally. The follow-up visits with somatosensory testing took place at 2 weeks, 6 weeks, 3 months and 6 months. When evaluated as means of the results, warm and cold thresholds were significantly elevated in the affected dermatome from the initial visit until 3 and 6 months, respectively. By contrast, heat pain thresholds were lowered at the initial visit but normalized by 2 weeks, and tactile thresholds remained unchanged. These threshold changes were associated neither with further development of PHN nor each other. It is concluded that measurement of somatosensory perception thresholds in early stages of HZ shows evidence of impaired neural function but is not helpful in predicting which patient will go on to develop PHN. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

A retrospective analysis of long-term efficacy of percutaneous radiofrequency thermocoagulation of the trigeminal ganglion or root for the relief of trigeminal neuralgia was carried out in our unit. From the medical records and questionnaires, outcomes of 108 procedures performed in 81 patients from January 1986 to December 1990 were obtained with a follow-up period of 6-11 years. The initial success rate was 87% and the probability of remaining pain-free 1, 2 and 11 years after the procedure was 65, 49 and 26%, respectively. Patients with typical symptoms had a better long-term efficacy than those with atypical presentations, and patients who had not undergone a previous surgical procedure also had a better outcome. There was no mortality in this series. Common adverse effects included dysaesthesia in 20 patients, corneal numbness in 12 patients and masseter weakness in three patients.

Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of lamotrigine was 400 mg. Lamotrigine was superior to placebo (P = 0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on lamotrigine compared with placebo. Global evaluations further suggested that patients did better on lamotrigine than placebo (P = 0.025). The adverse reactions with both lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that lamotrigine has antineuralgic properties.

Noninvasive quantitative somatosensory tests were used to measure sensory perception thresholds on the faces of 26 patients with idiopathic trigeminal neuralgia. The affected divisions were determined by the presence of trigger zones. Elevations of thresholds of sensations subserved by both large- and small-diameter fibers were found both in the affected and in the unaffected adjacent divisions when compared with the healthy side. The findings are interpreted as further evidence of combined peripheral and central pathologic conditions in idiopathic trigeminal neuralgia.

We studied 31 patients with acute herpes zoster (AHZ) less than 28 days' duration. Clinical characteristics (pain, allodynia, course of disease) and somatosensory perception thresholds (thermal discrimination, hot pain, and vibration) of the affected dermatome and the contralateral homologous area were assessed. Touch-evoked allodynia was found in 17 (55%) and dysesthesia in a further 5 (16%). Thermal and vibration perception thresholds demonstrated significant elevations when compared to the contralateral side. Thermal threshold abnormalities were significantly associated with the prevalence of postherpetic neuralgia (PHN) at 3 months. The effect of nerve blockade was less favorable on allodynia than spontaneous pain. The results of possible pathophysiological mechanisms are discussed.