Publications
221 results found
Payne CE, Brown AR, Theile JW, et al., 2015, A novel selective and orally bioavailable Na<sub>v</sub>1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 172, Pages: 2654-2670, ISSN: 0007-1188
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- Citations: 52
Ostenfeld T, Krishen A, Lai RY, et al., 2015, A Randomized, Placebo-controlled Trial of the Analgesic Efficacy and Safety of the p38 MAP Kinase Inhibitor, Losmapimod, in Patients With Neuropathic Pain From Lumbosacral Radiculopathy, CLINICAL JOURNAL OF PAIN, Vol: 31, Pages: 283-293, ISSN: 0749-8047
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- Citations: 27
Lopez-Cordoba A, Joensson P, Babakinejad B, et al., 2015, SICM-Based Nanodelivery System for Local TRPV1 Stimulation, 59th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 332A-332A, ISSN: 0006-3495
Roblin D, Yosipovitch G, Boyce B, et al., 2015, Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis, ACTA DERMATO-VENEREOLOGICA, Vol: 95, Pages: 542-548, ISSN: 0001-5555
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- Citations: 86
Danser AHJ, Anand P, 2014, The Angiotensin II Type 2 Receptor for Pain Control, CELL, Vol: 157, Pages: 1504-1506, ISSN: 0092-8674
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- Citations: 23
Rice ASC, Dworkin RH, McCarthy TD, et al., 2014, EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial, The Lancet, Vol: 383, Pages: 1637-1647, ISSN: 0140-6736
BackgroundExisting treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT 2R) is a new target for neuropathic pain. EMA401, a highly selective AT 2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia.MethodsIn this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22–89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22–28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987.Findings92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores −2·29 [SD 1·75] vs −1·60 [1·66]; difference of adjusted least square means −0·69 [SE 0·25]; 95% CI −1·19 to −0·20; p=0·0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatme
Libri V, Gibbs JSR, Pinato DJ, et al., 2014, Capsaicin 8% patch for treprostinil subcutaneous infusion site pain in pulmonary hypertension patients, BRITISH JOURNAL OF ANAESTHESIA, Vol: 112, Pages: 337-347, ISSN: 0007-0912
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- Citations: 2
Babakinejad B, Joensson P, Lopez Cordoba A, et al., 2013, Local Delivery of Molecules from a Nanopipette for Quantitative Receptor Mapping on Live Cells, ANALYTICAL CHEMISTRY, Vol: 85, Pages: 9333-9342, ISSN: 0003-2700
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- Citations: 59
Anand U, Facer P, Yiangou Y, et al., 2013, Angiotensin II type 2 receptor (AT(2)R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons, European Journal of Pain, Vol: 17, Pages: 1012-1026, ISSN: 1532-2149
BackgroundThe angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration.MethodsWe used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence.ResultsAT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas.ConclusionsAT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.
Ostenfeld T, Krishen A, Lai RY, et al., 2013, Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study, EUROPEAN JOURNAL OF PAIN, Vol: 17, Pages: 844-857, ISSN: 1090-3801
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- Citations: 40
Narayanaswamy H, Facer P, Misra VP, et al., 2012, A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies, JOURNAL OF CLINICAL NEUROSCIENCE, Vol: 19, Pages: 1490-1496, ISSN: 0967-5868
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- Citations: 46
Birch R, Eardley WGP, Ramasamy A, et al., 2012, Nerve injuries sustained during warfare PART I - EPIDEMIOLOGY, JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME, Vol: 94B, Pages: 523-528, ISSN: 0301-620X
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- Citations: 55
Birch R, Misra P, Stewart MPM, et al., 2012, Nerve injuries sustained during warfare: part II: Outcomes., J Bone Joint Surg Br, Vol: 94, Pages: 529-535
The outcomes of 261 nerve injuries in 100 patients were graded good in 173 cases (66%), fair in 70 (26.8%) and poor in 18 (6.9%) at the final review (median 28.4 months (1.3 to 64.2)). The initial grades for the 42 sutures and graft were 11 good, 14 fair and 17 poor. After subsequent revision repairs in seven, neurolyses in 11 and free vascularised fasciocutaneous flaps in 11, the final grades were 15 good, 18 fair and nine poor. Pain was relieved in 30 of 36 patients by nerve repair, revision of repair or neurolysis, and flaps when indicated. The difference in outcome between penetrating missile wounds and those caused by explosions was not statistically significant; in the latter group the onset of recovery from focal conduction block was delayed (mean 4.7 months (2.5 to 10.2) vs 3.8 months (0.6 to 6); p = 0.0001). A total of 42 patients (47 lower limbs) presented with an insensate foot. By final review (mean 27.4 months (20 to 36)) plantar sensation was good in 26 limbs (55%), fair in 16 (34%) and poor in five (11%). Nine patients returned to full military duties, 18 to restricted duties, 30 to sedentary work, and 43 were discharged from military service. Effective rehabilitation must be early, integrated and vigorous. The responsible surgeons must be firmly embedded in the process, at times exerting leadership.
Carlstedt T, Misra VP, Papadaki A, et al., 2012, Return of spinal reflex after spinal cord surgery for brachial plexus avulsion injury, JOURNAL OF NEUROSURGERY, Vol: 116, Pages: 414-417, ISSN: 0022-3085
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- Citations: 12
Birch R, Misra P, Stewart MP, et al., 2012, Nerve injuries sustained during warfare Part II – Outcomes, Journal of Bone Joint Surgery Br., Pages: 529-535
Anand P, Shenoy R, Palmer JE, et al., 2011, Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury, EUROPEAN JOURNAL OF PAIN, Vol: 15, Pages: 1040-1048, ISSN: 1090-3801
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- Citations: 116
Shenoy R, Roberts K, Papadaki A, et al., 2011, Functional MRI brain imaging studies using the Contact Heat Evoked Potential Stimulator (CHEPS) in a human volunteer topical capsaicin pain model., Journal of Pain Research, Vol: 4, Pages: 365-371, ISSN: 1178-7090
Acute application of topical capsaicin produces spontaneous burning and stinging pain similar to that seen in some neuropathic states, with local hyperalgesia. Use of capsaicin applied topically or injected intradermally has been described as a model for neuropathic pain, with patterns of activation in brain regions assessed using functional magnetic resonance imaging (fMRI) and positron emission tomography. The Contact Heat Evoked Potential Stimulator (CHEPS) is a noninvasive clinically practical method of stimulating cutaneous A-delta nociceptors. In this study, topical capsaicin (1%) was applied to the left volar forearm for 15 minutes of twelve adult healthy human volunteers. fMRI scans and a visual analog pain score were recorded during CHEPS stimulation precapsaicin and postcapsaicin application. Following capsaicin application there was a significant increase in visual analog scale (mean ± standard error of the mean; precapsaicin 26.4 ± 5.3; postcapsaicin 48.9 ± 6.0; P < 0.0001). fMRI demonstrated an overall increase in areas of activation, with a significant increase in the contralateral insular signal (mean ± standard error of the mean; precapsaicin 0.434 ± 0.03; postcapsaicin 0.561 ± 0.07; P = 0.047). The authors of this paper recently published a study in which CHEPS-evoked A-delta cerebral potential amplitudes were found to be decreased postcapsaicin application. In patients with neuropathic pain, evoked pain and fMRI brain responses are typically increased, while A-delta evoked potential amplitudes are decreased. The protocol of recording fMRI following CHEPS stimulation after topical application of capsaicin could be combined with recording of evoked potentials to provide a simple, rapid, and robust volunteer model to develop novel drugs for neuropathic pain.
Yiangou Y, Anand U, Otto WR, et al., 2011, Increased levels of SV2A botulinum neurotoxin receptor in clinical sensory disorders and functional effects of botulinum toxins A and E in cultured human sensory neurons, Journal of Pain Research, Vol: 2011, Pages: 347-355, ISSN: 1178-7090
Background: There is increasing evidence that botulinum neurotoxin A may affect sensory nociceptor fibers, but the expression of its receptors in clinical pain states, and its effects in human sensory neurons, are largely unknown.Methods: We studied synaptic vesicle protein subtype SV2A, a receptor for botulinum neurotoxin A, by immunostaining in a range of clinical tissues, including human dorsal root ganglion sensory neurons, peripheral nerves, the urinary bladder, and the colon. We also determined the effects of botulinum neurotoxins A and E on localization of the capsaicin receptor, TRPV1, and functional sensitivity to capsaicin stimuli in cultured human dorsal root ganglion neurons.Results: Image analysis showed that SV2A immunoreactive nerve fibers were increased in injured nerves proximal to the injury (P = 0.002), and in painful neuromas (P = 0.0027); the ratio of percentage area SV2A to neurofilaments (a structural marker) was increased proximal to injury (P = 0.0022) and in neuromas (P = 0.0001), indicating increased SV2A levels in injured nerve fibers. In the urinary bladder, SV2A nerve fibers were found in detrusor muscle and associated with blood vessels, with a significant increase in idiopathic detrusor overactivity (P = 0.002) and painful bladder syndrome (P = 0.0087). Colon biopsies showed numerous SV2A-positive nerve fibers, which were increased in quiescent inflammatory bowel disease with abdominal pain (P = 0.023), but not in inflammatory bowel disease without abdominal pain (P = 0.77) or in irritable bowel syndrome (P = 0.13). In vitro studies of botulinum neurotoxin A-treated and botulinum neurotoxin E-treated cultured human sensory neurons showed accumulation of cytoplasmic vesicles, neurite loss, and reduced immunofluorescence for the heat and capsaicin receptor, TRPV1. Functional effects included dose-related inhibition of capsaicin responses on calcium imaging after acute treatment with botulinum neurotoxins A and E.Conclusion: Differential
Keh SM, Facer P, Yehia A, et al., 2011, The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis., Rhinology, Vol: 49, Pages: 453-457, ISSN: 0300-0729
BACKGROUND: Menthol and cold sensation trigger symptoms and reflex responses in the upper airway, but the underlying molecular mechanisms are unknown. We have therefore studied nerve fibres expressing the menthol and cold receptor TRPM8 in normal human mucosa, and in rhinitis. TRPM8 nerve fibres were compared with those expressing other TRP receptors including TRPV1 (capsaicin and heat receptor), and TRPA1 (mechano-cold receptor). METHODS: Immunohistology and image-analysis were used to study TRP receptors in biopsies of nasal turbinate from control subjects, patients with allergic rhinitis, and non-allergic rhinitis. RESULTS: TRPM8-immunoreactive nerve fibres were observed in the sub-epithelium, and were profuse around blood vessels in deeper regions, where they were markedly greater in number than TRPV1+ fibers. Image analysis of TRPM8 in sub-epithelial and vascular regions showed no significant differences between control and the rhinitis patient groups. TRPA1-immunoreactivity was weak and seen rarely in nerve fibres. CONCLUSION: We show that TRPM8 nerve fibres are abundant in nasal mucosa particularly around blood vessels, and may mediate neurovascular reflexes. TRPM8 antagonists deserve consideration for therapeutic trial in rhinitis.
Keh SM, Facer P, Yehia A, et al., 2011, The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis, RHINOLOGY, Vol: 49, Pages: 453-457, ISSN: 0300-0729
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- Citations: 35
Anand P, Bley K, 2011, Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch, British Journal of Anaesthesia, Vol: 107, Pages: 490-502, ISSN: 0007-0912
Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug–drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as ‘defunctionalization’ of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies.
McNamee KE, Alzabin S, Hughes JP, et al., 2011, IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration, PAIN, Vol: 152, Pages: 1838-1845, ISSN: 0304-3959
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- Citations: 39
Roberts K, Shenoy R, Anand P, 2011, A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde, JOURNAL OF CLINICAL NEUROSCIENCE, Vol: 18, Pages: 926-932, ISSN: 0967-5868
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- Citations: 40
Facer P, Punjabi PP, Abrari A, et al., 2011, Localisation of SCN10A Gene Product Na<sub>v</sub>1.8 and Novel Pain-Related Ion Channels in Human Heart, INTERNATIONAL HEART JOURNAL, Vol: 52, Pages: 146-152, ISSN: 1349-2365
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- Citations: 52
George RS, Yacoub M, Facer P, et al., 2011, Correlation of Pre-Implant Norepinephrine Transporter Levels with Myocardial Recovery during Left Ventricular Assist Device Support, 31st Annual Meeting and Scientific Sessions on International-Society-for-Heart-and-Lung-Transplantation, Publisher: ELSEVIER SCIENCE INC, Pages: S212-S213, ISSN: 1053-2498
Facer P, Punjabi PP, Abrari A, et al., 2011, Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart., Int Heart J, Vol: 52, Pages: 146-152
We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.
Anand U, Otto WR, Anand P, 2010, Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons, Molecular Pain, Vol: 6, ISSN: 1744-8069
Background: Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests astingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy.Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing revealscold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatmentin cultured adult rat DRG neurons.Results: 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and numberof neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20μg/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u.,n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin(TRPV1 agonist), responses after acute 20 μg/ml oxaliplatin treatment where the second of paired capsaicinresponses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test,P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptoragonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses.Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004,unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control(85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected.Conclusions: Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which maycause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2agonists, to alleviate the n
George RS, Facer P, Yacoub MH, et al., 2010, Higher Implant Norepinephrine Transporter Levels in the Myocardium are Associated with Myocardial Recovery during Left Ventricular Assist Device Support, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Beneng K, Renton T, Yilmaz Z, et al., 2010, Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp, JOURNAL OF CLINICAL NEUROSCIENCE, Vol: 17, Pages: 1476-1479, ISSN: 0967-5868
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- Citations: 11
Elliot D, Lloyd M, Hazari A, et al., 2010, Relief of the pain of neuromas-in-continuity and scarred median and ulnar nerves in the distal forearm and wrist by neurolysis, wrapping in vascularized forearm fascial flaps and adjunctive procedures., J Hand Surg Eur Vol, Vol: 35, Pages: 575-582
This prospective study reports treatment by neurolysis then wrapping the nerves in vascularized forearm fascia and, when necessary, adjunctive procedures of twelve median and two ulnar nerves in continuity in the distal forearm with neurogenic pain. Preoperatively, all 14 patients had severe pain in at least one of the five modalities of pain analysed. There was complete resolution of all modalities of pain in eight of 14 patients following neurolysis and fascial nerve wrap surgery and two more patients had only mild pain in one or two modalities. After the addition of wrist pinning or arthrodesis alone or in conjunction with selective division of flexor tendons in four patients, there was complete resolution of all modalities of pain in nine of 14 patients. A further three patients had mild pain in three or less modalities and only one patient continued to have severe pain in one modality.
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