Tratamiento del Dolor Reunión conjunta SCBMI – SCD

Dolor Neuropático

____________________________ Dra. CARME BATET GABARRÓ

CapUnitatdeTractamentdeDolor

ConsorciSanitariIntegral

RESEARCH ARTICLE Open Access

Effectiveness of the capsaicin 8% patch inthe management of peripheral neuropathicpain in European clinical practice: theASCEND studyColette Mankowski1, Chris D. Poole1, Etienne Ernault2*, Roger Thomas3, Ellen Berni3, Craig J. Currie4,Cecil Treadwell1, José I. Calvo5, Christina Plastira6, Eirini Zafeiropoulou6 and Isaac Odeyemi1

Abstract

Background: In randomised studies, the capsaicin 8% patch has demonstrated effective pain relief in patients withperipheral neuropathic pain (PNP) arising from different aetiologies.

Methods: ASCEND was an open-label, non-interventional study of patients with non-diabetes-related PNP whoreceived capsaicin 8% patch treatment, according to usual clinical practice, and were followed for ≤52 weeks.Co-primary endpoints were percentage change in the mean numeric pain rating scale (NPRS) ‘average dailypain’ score from baseline to the average of Weeks 2 and 8 following first treatment; and median time fromfirst to second treatment. The primary analysis was intended to assess analgesic equivalence betweenpost-herpetic neuralgia (PHN) and other PNP aetiologies. Health-related quality of life (HRQoL, using EQ-5D),Patient Global Impression of Change (PGIC) and tolerability were also assessed.

Results: Following first application, patients experienced a 26.6% (95% CI: 23.6, 29.62; n = 412) reduction inmean NPRS score from baseline to Weeks 2 and 8. Equivalence was demonstrated between PHN and theneuropathic back pain, post-operative and post-traumatic neuropathic pain and ‘other’ PNP aetiologysubgroups. The median time from first to second treatment was 191 days (95% CI: 147, 235; n = 181).Forty-four percent of all patients were responders (≥30% reduction in NPRS score from baseline to Weeks 2and 8) following first treatment, and 86.9% (n = 159/183) remained so at Week 12. A sustained pain responsewas observed until Week 52, with a 37.0% (95% CI: 31.3, 42.7; n = 176) reduction in mean NPRS score frombaseline. Patients with the shortest duration of pain (0–0.72 years) experienced the highest pain responsefrom baseline to Weeks 2 and 8. Mean EQ-5D index score improved by 0.199 utils (responders: 0.292 utils)from baseline to Week 2 and was maintained until Week 52. Most patients reported improvements in PGICat Week 2 and at all follow-up assessments regardless of number of treatments received. Adverse eventswere primarily mild or moderate reversible application site reactions.

Conclusion: In European clinical practice, the capsaicin 8% patch provided effective and sustained pain relief,substantially improved HRQoL, improved overall health status and was generally well tolerated in a heterogeneousPNP population.

Trial registration: NCT01737294 Date of registration - October 22, 2012.

Keywords: Capsaicin 8% patch, Neuropathy, Pain management, Peripheral neuropathic pain, Topical analgesic,Numeric pain rating scale, Health-related quality of life

* Correspondence: etienne.ernault@astellas.com2Astellas Pharma Europe B.V., Leiden, The NetherlandsFull list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Mankowski et al. BMC Neurology (2017) 17:80 DOI 10.1186/s12883-017-0836-z

The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations

Shannon M. Smitha, Robert H. Dworkina,b, Dennis C. Turkc, Ralf Barond, Michael Polydefkise, Irene Traceyf, David Borsookg, Robert R. Edwardsh, Richard E. Harrisi, Tor D. Wagerj, Lars Arendt-Nielsenk, Laurie B. Burkel, Daniel B. Carrm, Amy Chappelln, John T. Farraro, Roy Freemanp, Ian Gilronq, Veeraindar Golir, Juergen Haeusslers, Troels Jensent, Nathaniel P. Katzu, Jeffrey Kentv, Ernest A. Kopeckyw, David A. Leex, William Maixnery, John D. Markmanz, Justin C. McArthurg, Michael P. McDermottaa, Lav Parvathenaniab, Srinivasa N. Rajaac, Bob A. Rappaportad, Andrew S. C. Riceae, Michael C. Rowbothamaf, Jeffrey K. Tobiasag, Ajay D. Wasanah, and James WitteraiaDepartment of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USAbDepartment of Neurology, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USAcDepartment of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USAdDepartment of Neurology, Universitaetsklinikum Schleswig-Holstein, Kiel, GermanyeDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USAfNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UKgCenter for Pain and the Brain, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USAhDepartments of Anesthesiology, Brigham & Women’s Hospital, Boston, MA, USAiDepartment of Anesthesiology and Internal Medicine, University of Michigan, Ann Arbor, MI, USAjDepartments of Psychology and Neuroscience, University of Colorado, Boulder, Boulder, CO, USA

*Corresponding author. Tel.: +1 585 273 2382; fax: +1 585 244 7271; shannon1_smith@urmc.rochester.edu (S.M. Smith). DisclosuresThe views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. Preparation of background literature reviews and the article was supported by ACTTION. No funding from any outside source was received for the meeting, nor the literature reviews and article preparation. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred.

HHS Public AccessAuthor manuscriptJ Pain. Author manuscript; available in PMC 2017 July 01.

Published in final edited form as:J Pain. 2017 July ; 18(7): 757–777. doi:10.1016/j.jpain.2017.02.429.

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Neuropathic pain

Luana Colloca1, Taylor Ludman1, Didier Bouhassira2, Ralf Baron3, Anthony H. Dickenson4, David Yarnitsky5, Roy Freeman6, Andrea Truini7, Nadine Attal8, Nanna B. Finnerup9, Christopher Eccleston10,11, Eija Kalso12, David L. Bennett13, Robert H. Dworkin14, and Srinivasa N. Raja15

1Department of Pain and Translational Symptom Science, School of Nursing and Department of Anesthesiology School of Medicine, University of Maryland, 655 West Lombard Street, 21201 Baltimore, Maryland, USA 2INSERM, Unit 987, Ambroise Paré Hospital, UVSQ, Boulogne Billancourt, France 3Department of Neurology, Division of Neurological Pain Research and Therapy, Klinik fur Neurologie Christian-Albrechts-Universitat Kiel, Kiel, Germany 4Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK 5Department of Neurology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel 6Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 7Department of Neurology and Psychiatry, Sapienza University, Rome, Italy 8Pain Evaluation and Treatment Centre of Hôpital Ambroise Paré, Paris, France 9Department of Clinical Medicine — The Danish Pain Research Center, Aarhus University, Aarhus, Denmark 10Centre for Pain Research, University of Bath, Bath, UK 11Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium 12Division of Pain Medicine,

Correspondence to L.C. Department of Pain and Translational Symptom Science, School of Nursing and Department of Anesthesiology School of Medicine, University of Maryland, 655 West Lombard Street, 21201 Baltimore, Maryland, USA. colloca@son.umaryland.edu. Author contributionsIntroduction (L.C. and T.L.); Epidemiology (D.B.); Mechanisms/ pathophysiology (A.H.D., L.C., D.Y. and R.F.); Diagnosis, screening and prevention (R.B., A.T. and R.H.D.); Management (N.A., N.B.F, S.N.R. and C.E.); Quality of life (E.K.); Outlook (R.H.D. and D.L.B.); Overview of the Primer (L.C.).Competing interestsL.C. has received lecture honoraria (Georgetown University and Stanford University) and has acted as speaker or consultant for Grünenthal and Emmi Solution. R.B. is an industry member of AstraZeneca, Pfizer, Esteve, UCB Pharma, Sanofi Aventis, Grünenthal, Eli Lilly and Boehringer Ingelheim; has received lecture honoraria from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD and Seqirus; and has served as a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim Pharma, Astellas, Desitin, Teva Pharma, BayerSchering, MSD, Novartis, Bristol-Myers Squibb, Biogen idec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Genentech, Galapagos NV and Kyowa Hakko Kirin. A.H.D. has acted as speaker or consultant forSeqirus, Grünenthal, Allergan and Mundipharma. D.B. has acted as a consultant for Grünenthal, Pfizer and Indivior. D.L.B. has acted as a consultant for Abide, Eli Lilly, Mundipharma, Pfizer and Teva. D.Y. received a lecture honorarium from Pfizer and holds equity in BrainsGate and Theranica. R.F. has acted as an advisory board member for Abide, Astellas, Biogen, Glenmark, Hydra, Novartis and Pfizer. A.T. has received research funding, lecture honoraria and acted as speaker or consultant for Mundipharma, Pfizer, Grünenthal and Angelini Pharma. N.A. has received honoraria for participation in advisory boards or speaker bureau by Astellas, Teva, Mundipharma, Johnson and Johnson, Novartis and Sanofi Pasteur MSD. N.B.F. has received honoraria for participation in advisory boards from Teva Pharmaceuticals, Novartis and Grünenthal, and research support from EUROPAIN Investigational Medicines Initiative (IMI). E.K. has served on the advisory boards of Orion Pharma and Grünenthal, and received lecture honoraria from Orion Pharma and AstraZeneca. R.H.D. has received research grants and contracts from the US FDA and the US NIH, and compensation for activities involving clinical trial research methods from Abide, Aptinyx, Astellas, Boston Scientific, Centrexion, Dong-A, Eli Lilly, Glenmark, Hope, Hydra, Immune, Novartis, NsGene, Olatec, Phosphagenics, Quark, Reckitt Benckiser, Relmada, Semnur, Syntrix, Teva, Trevena and Vertex. S.N.R. has received a research grant from Medtronic Inc. and honoraria for participation in advisory boards of Allergan, Daiichi Sankyo, Grünenthal USA Inc. and Lexicon Pharmaceuticals. C.E. and T.L. declare no competing interests.

HHS Public AccessAuthor manuscriptNat Rev Dis Primers. Author manuscript; available in PMC 2017 March 29.

Published in final edited form as:Nat Rev Dis Primers. ; 3: 17002. doi:10.1038/nrdp.2017.2.

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Research Paper

Peripheral neuropathic pain: a mechanism-relatedorganizing principle based on sensory profilesRalf Barona,*, Christoph Maierb, Nadine Attalc,d, Andreas Bindera, Didier Bouhassirac,d, Giorgio Cruccue,Nanna B. Finnerupf, Maija Haanpääg,h, Per Hanssoni,j, Philipp Hüllemanna, Troels S. Jensenf, Rainer Freynhagenk,Jeffrey D. Kennedyl, Walter Magerlm, Tina Mainkab,n, Maren Reimera, Andrew S.C. Riceo, Märta Segerdahlp,q,Jordi Serrar, Sören Sindrups, Claudia Sommert, Thomas Tölleu, Jan Vollertb,m, Rolf-Detlef Treedem, on behalf of theGerman Neuropathic Pain Research Network (DFNS), and the EUROPAIN, and NEUROPAIN consortia

AbstractPatients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiologicalmechanisms, andhence subgroupswith different sensory profilesmight responddifferently to treatment. The aimof the investigationwasto identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain).Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathicpain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Threedistinct subgroupswith characteristic sensory profileswere identified and replicated.Cluster 1 (sensory loss, 42%) showeda loss of smalland large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized bypreserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3(mechanical hyperalgesia, 24%)was characterizedby a loss of small fiber function in combinationwith pinprick hyperalgesia anddynamicmechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgroupingpatients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related topathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Keywords: Neuropathic pain, Sensory signs, Clinical trials, QST, Epidemiology

1. Introduction

Neuropathic pain syndromes develop after a lesion or diseaseaffecting the somatosensory nervous system.22,58 Despiteadvances in understanding the complex neurobiology of pain,the pharmacological management of these syndromesremains insufficient and several promising drugs have failed

in late-stage development.21,35 Thus, there is a need to predicttreatment responders both for clinical practice, in which evenfirst-line treatments are beneficial in less than 50% of patients,and for clinical trial design, in which a negative outcomemay bedue to a low responder rate rather than uniform inefficacy of thetreatment.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.a Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany, b Department ofPain Medicine, BG University Hospital Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany, c INSERM U-987, Centre d’Evaluation et de Traitementde la Douleur, CHU Ambroise Paré, Boulogne-Billancourt, France, d Université Versailles-Saint-Quentin, Versailles, France, e Department of Neurology andPsychiatry, Sapienza University, Roma, Italy, f Department of Neurology, Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark, g HelsinkiUniversity Central Hospital, Helsinki, Finland, h Etera Mutual Pension Insurance Company, Helsinki, Finland, i Department of Pain Management and Research,Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway, j Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm,Sweden, k Department of Anaesthesiology, Critical Care Medicine, Pain Therapy & Palliative Care, Pain Center Lake Starnberg, Benedictus Hospital Tutzing, Tutzing,Germany, and Klinik für Anästhesie, Technische Universität München, Munich, Germany, l Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis,IN, USA., m Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim CBTM, Medical Faculty Mannheim, Heidelberg University,Mannheim, Germany, n Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, o Pain Research, Department of Surgeryand Cancer, Imperial College, London, United Kingdom, p Clinical R&D Neurology, Lundbeck A/S, Copenhagen, Denmark, q Department of Physiology andPharmacology, Karolinska Institute, Stockholm, Sweden, r Neuroscience Technologies SLP, Barcelona, Spain, s Department of Neurology, Odense UniversityHospital, Odense, Denmark, t Department of Neurology, University Hospital Würzburg, Würzburg, Germany, u Department of Neurology, Klinikum rechts der Isar,Technische Universität München, Munich, Germany

*Corresponding author. Address: Division of Neurological Pain Research and Therapy, Dept. of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, House 41,Arnold-Heller-Strasse 3, 24105 Kiel, Germany. Tel.: 149 431 500 23805; fax: 149 431 500 23914. E-mail address: r.baron@neurologie.uni-kiel.de (R. Baron).

PAIN 158 (2017) 261–272

© 2016 International Association for the Study of Pain. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-NoDerivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or usedcommercially without permission from the journal.

http://dx.doi.org/10.1097/j.pain.0000000000000753

February 2017·Volume 158·Number 2 www.painjournalonline.com 261Copyright ! 2017 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.

Research Paper

Peripheral neuropathic pain: a mechanism-relatedorganizing principle based on sensory profilesRalf Barona,*, Christoph Maierb, Nadine Attalc,d, Andreas Bindera, Didier Bouhassirac,d, Giorgio Cruccue,Nanna B. Finnerupf, Maija Haanpääg,h, Per Hanssoni,j, Philipp Hüllemanna, Troels S. Jensenf, Rainer Freynhagenk,Jeffrey D. Kennedyl, Walter Magerlm, Tina Mainkab,n, Maren Reimera, Andrew S.C. Riceo, Märta Segerdahlp,q,Jordi Serrar, Sören Sindrups, Claudia Sommert, Thomas Tölleu, Jan Vollertb,m, Rolf-Detlef Treedem, on behalf of theGerman Neuropathic Pain Research Network (DFNS), and the EUROPAIN, and NEUROPAIN consortia

AbstractPatients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiologicalmechanisms, andhence subgroupswith different sensory profilesmight responddifferently to treatment. The aimof the investigationwasto identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain).Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathicpain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Threedistinct subgroupswith characteristic sensory profileswere identified and replicated.Cluster 1 (sensory loss, 42%) showeda loss of smalland large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized bypreserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3(mechanical hyperalgesia, 24%)was characterizedby a loss of small fiber function in combinationwith pinprick hyperalgesia anddynamicmechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgroupingpatients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related topathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Keywords: Neuropathic pain, Sensory signs, Clinical trials, QST, Epidemiology

1. Introduction

Neuropathic pain syndromes develop after a lesion or diseaseaffecting the somatosensory nervous system.22,58 Despiteadvances in understanding the complex neurobiology of pain,the pharmacological management of these syndromesremains insufficient and several promising drugs have failed

in late-stage development.21,35 Thus, there is a need to predicttreatment responders both for clinical practice, in which evenfirst-line treatments are beneficial in less than 50% of patients,and for clinical trial design, in which a negative outcomemay bedue to a low responder rate rather than uniform inefficacy of thetreatment.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.a Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany, b Department ofPain Medicine, BG University Hospital Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany, c INSERM U-987, Centre d’Evaluation et de Traitementde la Douleur, CHU Ambroise Paré, Boulogne-Billancourt, France, d Université Versailles-Saint-Quentin, Versailles, France, e Department of Neurology andPsychiatry, Sapienza University, Roma, Italy, f Department of Neurology, Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark, g HelsinkiUniversity Central Hospital, Helsinki, Finland, h Etera Mutual Pension Insurance Company, Helsinki, Finland, i Department of Pain Management and Research,Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway, j Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm,Sweden, k Department of Anaesthesiology, Critical Care Medicine, Pain Therapy & Palliative Care, Pain Center Lake Starnberg, Benedictus Hospital Tutzing, Tutzing,Germany, and Klinik für Anästhesie, Technische Universität München, Munich, Germany, l Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis,IN, USA., m Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim CBTM, Medical Faculty Mannheim, Heidelberg University,Mannheim, Germany, n Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, o Pain Research, Department of Surgeryand Cancer, Imperial College, London, United Kingdom, p Clinical R&D Neurology, Lundbeck A/S, Copenhagen, Denmark, q Department of Physiology andPharmacology, Karolinska Institute, Stockholm, Sweden, r Neuroscience Technologies SLP, Barcelona, Spain, s Department of Neurology, Odense UniversityHospital, Odense, Denmark, t Department of Neurology, University Hospital Würzburg, Würzburg, Germany, u Department of Neurology, Klinikum rechts der Isar,Technische Universität München, Munich, Germany

*Corresponding author. Address: Division of Neurological Pain Research and Therapy, Dept. of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, House 41,Arnold-Heller-Strasse 3, 24105 Kiel, Germany. Tel.: 149 431 500 23805; fax: 149 431 500 23914. E-mail address: r.baron@neurologie.uni-kiel.de (R. Baron).

PAIN 158 (2017) 261–272

© 2016 International Association for the Study of Pain. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-NoDerivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or usedcommercially without permission from the journal.

http://dx.doi.org/10.1097/j.pain.0000000000000753

February 2017·Volume 158·Number 2 www.painjournalonline.com 261Copyright ! 2017 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.

Generalidades •  ElDNestácausadoporunalesiónoenfermedaddelSistemaSomatosensorial⇒permitelapercepción:Tacto,presión,dolor,temperatura,posición,movimiento,vibración.

•  Losnerviossomatosensorialessurgenen:piel,músculos,articulacionesyfascias•  incluyentermorreceptores,quimiorreceptores,terminacionespruritoralesynociceptoresqueenvíanseñalesamédulaespinal ⬇︎⬇︎⬇︎⬇︎⬇︎⬇︎eltálamorecibelaseñalyladirigealacortezacerebral.

•  LesionesoenfermedadesdelsistemaSomatosensorial⇒alatransmisiónalteradadeseñalessensorialesamédulaespinalycerebro.

•  NotodoslospacientesconneuropatíaperiféricaolesiónnerviosacentraldesarrollanDN•  EnlaDMlaprevalenciadelossíntomasdeDNfuedel21%enpacientesconneuropatíaclínica.

•  Esdifícilestimarlaincidenciayprevalenciadebidoalafaltadecriteriosdiagnósticossimplesparagrandesestudios.

•  Sehaestimadosobreestudiosrealizadosencentrosespecializadosconunenfoqueaafectaciones•  NPH,PND,DNpostquirúrgico,EM,lesióndelamédulaespinal,AVCyCáncer.

Generalidades •  Síntomasprincipales:

•  Quemazón,Sensacióneléctricaydoloraestímulosnodolorosos•  Persistenyrespondenescasamentealosanalgésicos.•  Aparecennormalmenteotrasalteraciones⇒delsueño,ansiedad,depresión

•  Lacalidaddevida,másdeterioradaenpacientesconDNcrónicoqueconDcrónicononeuropático

1.  EPIDEMIOLOGÍA•  LasradiculopatíalumbaresycervicalessonlacausamásfrecuentedeDNcrónico.•  Unaencuestadedolorsobre12000pacientescondolorcróniconociceptivo,revelóqueel

•  40%detodoslospacientesexperimentanalgunascaracterísticasdeDNcomoquemazón,entumecimientoyhormigueo,lospacientescondolorlumbaryradiculopatíasevieronparticularmenteafectados.

2.Mecanismos y Fisiopatología ______________________________________ 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2.1 CAUSAS Y DISTRIBUCIONES ____________________________________________________

•  ElDNCentraldebidoaenfermedadolesióndelamédulaespinalocerebro.•  Laenfermedadcerebrovascular(ACVvascularotraumática)•  enfermedadesneurodegenerativas(Parkinson).•  lesionesoenf.delamedulaespinal

•  ELDNPeriféricoinvolucrapredominantementefibrasAmielinizadascomolasfibrasA𝛽,A𝛿yfibrasCamielínicas

•  ElDNperiféricosepuedesubdividiren•  aquellosquetieneunadistribucióngeneralizada,simétrica,distal-proximal“guanteymedia”

•  DM,prediabetes,disfuc.metabólicas,infecciosas-HIV,lepra-,QT,inmune-GillainBarre-,Hereditarias–eritromelalgia-

•  aquellosconunadistribuciónfocal,involucra1omasnervios:NPH,CRPS2,postcirugia,radiculopatía

Figure 2. Neuroanatomical distribution of pain symptoms and sensory signs in neuropathic pain conditionsDistribution of pain and sensory signs in common peripheral and central neuropathic pain conditions. *Can sometimes be associated with central neuropathic pain. ‡Can sometimes be associated with peripheral neuropathic pain.

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Figure 1. The peripheral and central changes induced by nerve injury or peripheral neuropathyPreclinical animal studies have shown that damage to all sensory peripheral fibres (namely, Aβ, Aδ and C fibres; BOX 1) alters transduction and transmission due to altered ion channel function. These alterations affect spinal cord activity, leading to an excess of excitation coupled with a loss of inhibition. In the ascending afferent pathways, the sensory components of pain are via the spinothalamic pathway to the ventrobasal medial and lateral areas (1), which then project to the somatosensory cortex allowing for the location and intensity of pain to be perceived (2). The spinal cord also has spinoreticular projections and the dorsal column pathway to the cuneate nucleus and nucleus gracilis (3). Other limbic projections relay in the parabrachial nucleus (4) before contacting the hypothalamus and amygdala, where central autonomic function, fear and «anxiety are altered (5). Descending efferent pathways from the amygdala and hypothalamus (6) drive the periaqueductal grey, the locus coeruleus, A5 and A7 nuclei and the rostroventral medial medulla. These brainstem areas then project to the spinal cord through descending noradrenaline (inhibition via α2 adrenoceptors), and, in neuropathy, there is a loss of this control and increased serotonin descending excitation via 5-HT3 receptors (7). The changes induced by peripheral neuropathy on peripheral and central functions are shown. Adapted with permission from REF. 38, Mechanisms and management of diabetic painful distal symmetrical polyneuropathy, American Diabetes Association, 2013. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

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Mecanismos y Fisiopatología 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2. 2 CAMBIOS EN LA CONDUCCIÓN DEL DOLOR __________________________________________________________ Laneuropatíaperiféricaalteralaspropiedadeseléctricasdelosnerviossensoriales

1.  Enelnervioperiféricodespuésdeunalesión⇒seproduceunaactividadectópicaenlasfibrasaferentesprimarias⇒tieneunpapelclaveenlafisiopatologíadelDN

2.  Aniveldelasneuronasdelastadorsaldelamédulaespinal,sealteralatransmisióndelasseñalessensorialesytodoslosmecanismosdedesinhibiciónofacilitación.

3.  Seproducendesequilibriosentrelainformacióncentralexcitatoriaeinhibitoria

•  Enlaperiferia,lamédulaespinalyelcerebroseproduceunaumentodeexcitaciónyunapérdidadeinhibiciónàhiperexcitabilidad

Mecanismos y Fisiopatología 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2.3 ALTERACIONES DEL CANAL IÓNICO _____________________________________________ •  Laneuropatíacausaalteracionesenloscanalesiónicos(sodio,calcioypotasio)dentrodelosnerviosafectados:

1.  AumentodelaexpresiónylafuncióndeloscanalesdeNa⁺,elpapelcrucialdeloscanalesdesodiosedemuestraporlapérdidaogananciadedolor.

2.  PérdidadeloscanalesdeK⁺quenormalmentemodulanlaactividadneuronal

•  Siunafibraaferentesedesconectadelaperiferiaporunalesiónpuedegeneraractividadectópica

àComoconsecuenciaestasaferenciaspuedegenerardolorcontinuo,entumecimientoydolorevocado.

3.  AumentodelaexpresióndeloscanalesdeCa⁺⁺enlamédula⇒mayorliberaciónde

neurotransmisoresyunamayortransmisiónsinápticaexcitatoriaenelcircuitonociceptivo.

Mecanismos y Fisiopatología 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2.4 ALTERACIONES DE NEURONAS NOCICEPTIVAS DE SEGUNDO ORDEN ______________________________________________________________

•  Laexcitabilidadaumentadadelasneuronasespinalesincrementaotrasrespuestassensoriales:•  PermitealasfibrasaferentesA𝛽yA𝛿debajoumbralactivarneuronasnociceptivasdesegundoordenyademásexpandesuscamposreceptivosdetalmaneraqueunestímulodado⇒excitamasneuronasdesegundoorden⇒sensibilizacióncentral.

•  Ladescargacontinuadefibrasaferentesperiféricas,conliberacióndeAminoácidosyneuropéptidosexcitadoresconduceacambiospostsinápticosenlasneuronasdesegundoordenyaunexcesodeseñalesdebidoalafosforilacióndelN-metil-D-aspartato(NMDA).Estoscambiosdesegundoordenexplicanlaalodiniaysereflejanenunamayoractividadtalámicasensorial

•  Lahiperexcitabilidadtambiénpuedesercausadaporunapérdidadeneuronasinhibitoriasdeácido𝛾-aminobutírico(GABA)quepuedencambiarparaejerceraccionesexcitatoriasaniveldecolumna

•  Tambiénhaycambiosfuncionales,menosbiencomprendidos,enlascélulasnoneuronalesdentrodelamédulaespinal,comomicrogliayastrocitos,quecontribuyenaldesarrollodehipersensibilidad

Mecanismos y Fisiopatología 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2.5 CAMBIOS DE MODULACIÓN INHIBITORIA _____________________________________________ •  EnelDNseproducen:Cambiosenlasneuronasdetransmisióndedolor,enlasinterneuronasinhibitoriasyenlossistemasdecontrolmoduladordescendente,quesondisfuncionalesàperoloquesegeneraydominaenlaneuropatíaeslatransmisiónexcitatoria

1.  LasproyeccionesalteradasalTálamo,CortezayRegionesLímbicasexplicanlosaltosíndicesdeansiedad,depresiónyproblemasdesueño.

2.  LaproyecciónalaCortezaCinguladayAmígdalaactivaloscontrolesdescendenteshacialasustanciagrisperiacueductal(centroparalamodulacióndescendente)àaltroncodelencéfaloyàactúansobrelaseñalespinaldelsistemanoradrenérgico.

3.  Perolasinhibicionesnoradrenérgicasdescendentes,mediadasporlosreceptores𝛼2-adrenérgicosestánatenuadasenelDN

4.  ElsistemanoradrenérgicoeselqueactivaeldiffuseNoxiusinhibitoricontrol(DNIC)controlesinhibitoriosdifusos,

queregulaloquellamamosModulaciónCondicionadaaldolor(CPM)eslainhibicióndeldoloratravésdelas

víasdescendentes.TantoDNICyelCMPsepierdentotaloparcialmenteenpacientesconDNrespectosanos

Mecanismos y Fisiopatología 1.  CAUSASYDISTRIBUCIONES2.  CAMBIOSENLACONDUCCIÓNDELDOLOR3.  ALTERACIONESDELCANALIÓNICO4.  ALTERACIONESDENEURONASNOCICEPTIVASDESEGUNDOORDEN5.  CAMBIOSDEMODULACIÓNINHIBITORIA6.  MECANISMOSDEMODULACIÓNDEDOLOR

2.6 MECANISMOS DE MODULACIÓN DE DOLOR ____________________________________________________ •  AlgunospacientesconDNestán↑afectadosyotros↓•  Ademásexisteunagranvariabilidadenlarespuestaalostratamientos.

•  UnfactorclaveenestavariabilidadeslaformacomosemodulaelmensajededolorenelSNC.

•  Laseñaldedolorpuedeaumentarseoreducirseamedidaqueasciende,desdesuentradaalastadorsalhastaquellegaalacortezacerebral.

•  HayinterferenciasquepuedenmodificarlarelaciónentreLesiónPeriférica-SíndromeDolor

•  LamayoríadepacientesconDNexpresanunperfildemodulacióndedolorpro-nociceptivoàlosmensajesdedolorysupercepciónaumentaenelSNC⟹porqué?

•  DebidoaunadisminucióndelainhibiciónendógenadescendenterepresentadaenelCPMConditionedPainModulationquesevuelvemenoseficientey/oaunafacilitaciónatravésdela

sensibilizacióndelasvíasdeldolorascendenteloquesellama,Sumacióntemporalincrementada

⟹enunoscasospuededominarunperfilpronociceptivoinhibitorioyenotrosunperfilfacilitador.

2.6 MECANISMOS DE MODULACIÓN DE DOLOR

•  ElperfildemodulacióndeDolorpuedepredecireldesarrolloyextensióndeldolorpostoperatoriocrónico*(PubMed27331347Pain.2016,PubMed22480803Pain.2012)

•  Pacientesquemuestranunperfilpronociceptivofacilitadoràpodríansertratadosporunfármacoquereducenlafacilitación⟹gabapentinoides

•  Pacientesqueexpresanunperfilpronociceptivoinhibitoriopodríansertratadosconunfármacoquemejoranlainhibiciónendógenacomo⟹inhibidoresdelarecaptacióndeserotonina-noradrenalina:DuloxetinayTapentadol

•  LospacientesqueexpresanunaCPMdisminuidayalavezunaSumacióntemporalaumentada,puedennecesitarunacombinacióndetratamientos

•  HayquetenerencuentaqueelperfildeModulacióndeDoloralteradodeunpacientepuederevertirsehacialanormalidadcuandosetrataeldolorotambiéncuandosetratalacausa…porej.conunaartroplastia.

•  LaModulacióndeldolorestámuyinfluenciadaporlaanalgesiainducidaporlasexpectativas,esdecirlaconfianzaydeseosdelpacienterespectoalproveedor,afectalarespuestaaltratamientodeldolorneuropático.

•  TodosestoshallazgosapuntanaunmecanismoinhibidordeldolorconimplicacionesdelfenotipadodepacientesconDN.Estomejoranuestraprácticaclínicaynuestraestrategiaparaoptimizarelmanejodeldolor.

Diagnóstico, cribado y prevención

1.  PRUEBASCONFIRMATORIASDEDAÑOENLASFIBRASNERVIOSAS

2.  PRIMERAEVALUACIÓNSENSORIAL

3.  PRUEBASSENSORIALESCUANTITATIVASQST–QUANTITATIVESENSORYTESTING

4.  PRUEBASNEUROFISIOLÓGICAS

5.  BIOPSIADEPIEL

6.  MICROSCOPIACONFOCALCORNEAL

7.  PREVENCIÓN

Mechanism / profile-based therapy

Sensory profile

Von Hehn, Baron and Woolf 2012

Diagnóstico, cribado y prevención __________________________________________________

•  Comodeterminarsiundoloresneuropáticoonociceptivo

1.  SilaHC,exploraciónfísicasugierepresenciadelesiónnerviosaoenfermedadneurológica,eldolorestárelacionadoconelloysudistribuciónsecorrespondeanivelneuroanatómico(utilizandoherramientasdemediciónvalidadas)eldolor⇒DNposible•  Tacto,pinchazo,presión,frio,calor,vibraciónnosdaInformaciónSomatosensorialvaloradacomo

Normal,disminuida,aumentada

2.  CuandomedianteunexamenclínicomedimoslossignossensorialesypruebassensorialescuantitativasmedianteQSTyherramientasvalidadas⇒DNprobable

3.  ElDNdefinitivorequiereunapruebadiagnósticaobjetiva:•  Biopsiadepiel.•  Pruebasneurofisiológicascuantificables•  Microscopiaconfocalcorneal

•  UnhallazgodeDNProbabledeberíaconduciraltratamiento

Cuestionarios DN4 PainDetect

•  PRUEBASSENSORIALESCUANTITATIVASQST–QUANTITATIVESENSORYTESTING

•  UtilizanestímulostérmicosymecánicosestandarizadosparaprobarevaluarlaperdidaylagananciaenlafuncióndelasfibrasA𝛽,A𝛿yC.

•  LaReddeInvestigaciónNeuropáticaAlemanapropusounabateríadepruebassensorialescuantitativasde13parámetrosparaidentificarlosfenotipossensorialesdepacientesconDN.

QST Profiling of signs: QST protocol / 13 parameters

__________________________________________________

•  PRUEBASNEUROFISIOLÓGICAS•  LasLEPpotencialesevocadosporláserconsideradolaherramientaneurofisiológicamásfiableparaevaluarlasfuncionesnociceptivas.•  LasestimulacionesporláseractivanselectivamentelosnociceptoresA𝛿yCenlascapassuperficialesdelapiel.

•  BIOPSIADEPIEL•  Seconsideralaherramientamássensibleparadiagnosticarneuropatíasdefibrapequeña.•  LapieltienefibrasamielínicasCyfibrasmielinizadaspequeñasA𝛿quepierdensuvainademielinaylleganaepidermiscomoterminacionesnerviosaslibres.

•  Sinembargo,larelaciónentrelosdatosdelabiopsiadepielyelDNaúnnoestáclara.

•  MICROSCOPIACONFOCALCORNEAL•  Técnicanoinvasivaqueestudiaeldañodelafibranerviosacorneal,A𝛿yCenpacientesconneuropatíasperiféricas.Altocosteyreducidadisponibilidad.

PRUEBASCONFIRMATORIASDEDAÑOENLASFIBRASNERVIOSAS

Diagnóstico, cribado y prevención __________________________________________________

7.PREVENCIÓN•  Lasintervencionesqueprevieneneldolorneuropáticopuedentenerunefectosustancialenlasaludpública

•  Llevarunestilodevidasaludableyeducaciónsobrelascondicionesdesaludquecausandolor,especialmenteenaquellosquetienenmayorriesgodedesarrollarDN.

•  Identificarfactoresderiesgo•  Lasestrategiasdeprevenciónprimariaincluyen,vacunasvivasatenuadascontraelHerpesZ,intervencionespreventivasalaspersonasqueestádesarrollandounaenfermedadquepuedecausarDN

•  Tratamientoperioperatorioparaprevenireldolorpostquirúrgico•  ManejoadecuadodecondicionesdesaludcomolaDM

Tratamiento •  INTERVENCIÓNMÉDICA•  TRATAMIENTOSFARMACOLÓGICOS

•  Primeralínea•  Segundalínea•  Terceralínea

•  TRATAMIENTOSEMERGENTES•  TERAPIASINTERVENCIONISTAS•  BLOQUEONEURONALEINYECCIONESDEESTEROIDES•  ESTIMULACIÓNDELAMÉDULAESPINAL•  GANGLIODELARAIZDORSAL,ESTIMULACIÓNDELNERVIOPERIFÉRICOYDELCAMPODELNERVIOPERIFÉRICO•  NEUROESTIMULACIÓNCORTICALEPIDURALYTRANSCRANEAL•  ESTIMULACIÓNCEREBRALPROFUNDA•  TERAPIASINTRATECALES•  TERAPIASFÍSICAS•  TERAPIASPSICOLÓGICAS

____________________________________________________________________________________________________ Fármaco Mecanismo Acción NNT (rango) Efectos Adversos Precauciones/Contraindicacs. ____________________________________________________________________________________________________ AntidepresivosTricíclicosNortiptilina Inhibiciónrecaptación 3.6(3-4.5) Somnolencia -Enf.Cardiaca,Glaucoma,

Desipramina monoaminas. EfectosAnticolinérgicos Adm.Próstata,Epilepsia

Amitriptilina BloqueoCanalesdeSodio Aumentodepeso -EvitarDosisAltasen>65y

Clomipramina EfectosAnticolinérgicos PacientesconAmiloidósis

Imipramina

________________________________________________________________________________________________________________________________

InhibidoresrecaptaciónNoradrenalina-SerotoninaDuloxetina Inh.RecaptacNA-Serotonina 6.4(5.2-8.2) Nausea,dolorabd,constipación -Alt.Hepática,Hipertensión

-Tramadol

Venlafaxina Inh.Recapc.Na-Serotonina 6.4(5.2-8.2) Nauseas,HTAadosisaltas -EnfCardíaca.HTA,Tramadol

________________________________________________________________________________________________________________________________

UniónCanalesdeCalcio𝛼2𝛿Gabapentina Actúaenlassubunidades𝛼2𝛿 6.3(5-8.4) Sedación,mareo, -ReducirdosisenInsf.Renal

Pregabalina delcanaldeCalciodisminuyendo 7.7(6.5-9.4) edemaperiférico,aumentopeso

Enacarbíl lasensibilizacióncentral 8.3(6.2-13)

________________________________________________________________________________________________________________________________

Prim

eraLíne

ade

Tratamientos

____________________________________________________________________________________________________ Fármaco Mecanismo Acción NNT (rango) Efectos Adversos Precauciones/Contraindicacs. ____________________________________________________________________________________________________ TratamientosTópicosLidocaína%parche BloqueaCanalesdeSodio --- Eritemalocal,picor,rash ninguno

________________________________________________________________________________________________________________________________

Capsaicinaparche Actúainhibiendoelflujodeiones 10.6(7.4-19) Dolor,eritema,picor Nosehanproducidoalteraciones

atravésdelamembrana AlgúncasodeHTA sensorialesendosisrepetidas

________________________________________________________________________________________________________________________________

Opioides________________________________________________________________________________________________________________________________

Tramadol AgonistaReceptor𝜇 Nausea,vómitoconstipación Historiaabusosustancias,

Inhibelarecaptacióndemonoaminas 4-7(3.6-6.7) mareo,somnolencia riesgosuicidio,antidepresivosen

Tapentadol pacientesedadavanzada

________________________________________________________________________________________________________________________________

MorfinayOxicodona AgonistasdelReceptor𝜇 4.3(3.4-5.8) Nausea,vómito,constipación, Historiadeabuso,riesgode

Oxicodonapuedeantagonizarel mareoysomnolencia suicidio,malusoalargoplazo

receptoropioide𝜅

_________________________________________________________________________________________________________________________________

Segund

aLíne

ade

Tratam

ientos

TerceraLíne

ade

Tratamientos

____________________________________________________________________________________________________ Fármaco Mecanismo Acción NNT (rango) Efectos Adversos Precauciones/Contraindicacs. ____________________________________________________________________________________________________

Neurotoxina

________________________________________________________________________________________________________________________________

ToxinaBotulínicaA Inhibidordelaliberaciónde 1.9(1.5-2.4) Dolorenpuntodepunción Hipersensibilidadeinfección

acetilcolina;efectospotenciales eneláreadedolor.

sobrelamecano-transduccióny

efectoscentraleseneldolorneuropático

_________________________________________________________________________________________________________________________________

NNTNumberneededtotreatparamejorarun50%iobtenerunrespondedormas,porencimadelgrupoplaceboocontrol

TerceraLíne

ade

Tratamiento

Tratamiento

•  TRATAMIENTOSEMERGENTES

•  AgentesdebloqueodeloscanalesdeSodioselectivos,antagonistasdelNav1.7yEMA401

•  UnantagonistatipoIIdelaAngiotensina,aunquetodavíaestáenfasepreclínica

•  Hayresultadosprometedoresconcélulasmadre

•  BloqueantedelreceptorSigma-1

TERAPIAS INTERVENCIONISTAS ____________________________________________________ •  BLOQUEONEURONALEINYECCIONESDEESTEROIDES

•  Inyecciónperineuraldecorticoidesproporcionaaliviotransitorioparaeldolorneuropáticoperiféricorelacionadocontraumaocompresión2

•  LosrevisionesymetanálisisdeEpiduralesenradiculopatíascervicalesylumbaresmostraronreduccióninmediatadeldolor,pero<3mesesynotuvieronefectossobrereduccióndelriesgodecirugíaposterior1,3,4.

•  LosCorticoidesyALEpiduralesrecibenunarecomendacióndébilparalaradiculopatíalumbaryelDNporzosteragudo1

•  EnCRPSlosbloqueossimpáticostienenevidenciadébilalargoplazo1,aunquesehanutilizadolosbloqueosdeGangliosimpáticoparatratarlosSDRC

•  1Dworkin,etal.RHInterventionalManagementofNerophaticPain2013;154:2249-2261(PubMed23748119)•  2BhatiaA,etal.PerineuralSteroidsfortraumaandcompression-relatedperipheralneurophaticpain.JAnaesth.2015;62:650-662(PubMed:25744141)•  3CohenSp,etal.EpiduralSteroids:acomprehensiveevidence-basedreview.RegAnesthPainMed2013;38:175-200(PubMed:23598728)•  4ChouR,etal.EpiduralCortcosteroidinyectionsorradiculopathyandspinalstenosis.AnnInternMed.2015;163:373-381(PubMed26302454)

Radiofrecuencia Radicular

TERAPIAS INTERVENCIONISTAS ____________________________________________________

•  ESTIMULACIÓNDELAMÉDULAESPINAL•  Inicialmenteseintrodujolaestimulacióndefibras𝛽comounaestrategiaparamodularlasseñalesdedolortransmitidasporlasfibrasCnomielinizadas.Laestimulaciónmasutilizadahasidoelpulsomonofásicodeondacuadrada(30-100Hz)queproducíaunaparestesiaenlazonadedolor*

•  Losparámetrosmasrecientescomolaráfaga(ráfagasde40Hzconpicosde500Hzporráfaga)ylaestimulacióndealtafrecuenciaproporcionaunaestimulaciónlibredeparestesiaymejorcontroldeldolor*

•  Losestudiosaleatorioshanmostradoevidenciadelaestimulaciónalargoplazocuandosecombinaconeltratamientomédicoyhademostradoresultadossostenidosalos24meses*

•  DosensayosaleatoriosenpacientesconPneuropatíadiabéticadolorosa⇒mejorcontroldeldolorymejorcalidaddevida*

•  LasdirectriceseuropeasactualesdanunarecomendacióndébilparalaestimulacióndelaMédulaespinal(combinadaconelttomédico),porejemploDNdiabético*

•  Suéxitodependedelaselecciónapropiadadelospacientesbasadaenlosrasgospsicológicos,fenotiposensorial,sensibilizacióncentralbajayCPMreducida*

•  *Collocaetal.NeuropathicPain,NatRevPrimers;3:17002,doi:10.1038/nrdp.2017.2.

Estimulación espinal

TERAPIAS INTERVENCIONISTAS __________________________________________________________

•  GANGLIODELARAIZDORSAL,ESTIMULACIÓNDELNERVIOPERIFÉRICOYDELCAMPODELNERVIOPERIFÉRICO

•  Neuroestimulacióndefibrasaferentesfueradelamédulaespinal-Gangliodelaraízdorsalylaestimulaciónsubcutáneadelcampodelnervioperiféricoproporcionadisminucióndel

dolorenvariosestadosdeDNCrónico,ejneuralgiaoccipitalyNPH*

•  UnestudiorandomizadoprospectivomulticéntricodemostróquelaestimulacióndelDRGproporcionó56%dedisminucióndeldolorconunatasaderespuestadel60%*

•  *LiemL.etal.OneyearoutcomesofspinalcordstimulationofDRGinchronicneuropathicpain.Neuromodulation.2015;18:41-48.

pubMed:25145467)

Tratamiento de Dolor Radicular Radiofrecuencia en el Ganglio de la Raíz Dorsal L5

DolorRadicularCervicalRadiofrecuenciadeGanglioscervicales

Dolor Discal i Dolor Radicular Radiofrecuencia Discal

Dolor Radicular por Fibrosis Epidural posterior a Laminectomía Epiduroscopia

NEUROESTIMULACIÓN CORTICAL EPIDURAL Y TRANSCRANEAL •  LaNeuroestimulacióncorticalpuedereducirlahiperactividadtalámicarelacionadaconeldoloroactivarlasvíasinhibitoriasdescendentes.

•  Laestimulacióndelacortezamotoraepidural(ECMS)reduceenel60-65%depacientesunadisminucióndolor>40%⇒Procedimientoneuroquirúrgico⇒colocaciónprecisadelelectrodosobrelacortezamotoradeláreadedolor.

•  TerapiasNoinvasivas•  EstimulaciónMagnéticaTranscranealrepetitiva(rTMS)•  Estimulacióndelacorrientedirectatranscraneal(tDCS)delacortezamotoraprecentral

•  Neuroestimulanáreasdelcerebroatravésdebobinasmagnéticasoelectrodosencuerocabelludo

•  DirectricesEuropeasactualesindicanrecomendacióndébilparaelusodeEMCSyrTMSenelDNcrónicorefractarioydetDCSparaeldolorneuropáticoperiférico*

•  *KumarKetal.PUBMed17845835)

Tratamiento ____________________________________________________

•  ESTIMULACIÓNCEREBRALPROFUNDAIntracraneal•  LaNICEreconocequepuedesereficazenalgunospacientesrefractariosaotrasformasdecontroldedolor

•  Laevidenciamuestrariesgospotencialessignificativoscomoconvulsionesintraoperatorias,fracturasdelplomoeinfeccionesycontrariamentealaNICElasdirectricesEuropeasactuales⇒recomendacionesnoconcluyentes.

•  TERAPIASINTRATECALES•  LaConferenciadeConsensoPoli-analgésicode2012destacóqueestaterapiaestáasociadaariesgosdemorbilidadymortalidadgravesyrealizórecomendacionesparareducirlaincidenciadeestosefectosadversosgraves.Lasrecomendacionessondeunconsensodeexpertos(PubMed22849581)

•  ÚnicosFármacosaprobadosporlaFDA:Morfina,Ziconitida.

Terapias Intratecales

•  TERAPIASFÍSICAS•  Ejercicio,fisioterapia,técnicasderepresentacióndelmovimientocomolaterapiaenespejoy/o

laimaginacióndemovimientoslibresdedolor,sonbeneficiososyefectivasenelmanejodelDN

•  TERAPIASPSICOLÓGICAS•  LaspersonasconDNnosonpasivas,intentanactivamentecambiarlascausasdedolorycambiar

supropiocomportamientoenrespuestaaldolor,sinembargo,estecambiosinayuda

terapéuticaparamuchospacientesesinalcanzable.

•  Laintervenciónpsicológicaestápensadaparapromoverelmanejodeldoloryreducirsus

consecuenciasadversas⇒LosmasimportantessonlaTerapiaCognitivaConductual(TCC)

Dolor neuropático y Diabetes

•  NeuropatíacrónicadolorosaenpacientesconDMesdel10-26%delosquepresentanneuropatía

•  Lospacientesdiabéticostienealteradoslasvíasdedolorperiféricasycentrales.•  Estudiosepidemiológicossugierenquepacientesconneuropatíarespectoalosqueno,tienendiferente:

•  Funcióncardiovascular,controlglucémico,peso,obesidad,circunferenciaabdominal,riesgodeenfvascularperiférica,nivelesdeTG,inestabilidaddeglucosaensangre,ademáspresentan

•  Alteradoelflujosanguíneoepineuraldelnvperiférico,microcirculacióndelapieldelpie,densidaddelafibraintraepidérmicaalterada,aumentodelavascularidadtalámicaydisfunciónautonómica.

•  Presentanlosnivelesdemetilglioxalaumentadosdebidoaglucolisisexcesivaydegradacióndisminuidadelaglioxalase.

•  Estemetabolitoalteralosnerviosperiféricosporque•  ActivaloscanalesdeNadependientesdevoltaje:Nav1.7yNav1.8•  Disminuyelaconducciónnerviosa,aumentalaliberacióndepéptidosrelacionadosconelgendelacalcitoninadelosnerviosyconducelahiperalgesiatérmicaymecánicaasociadaaladiabetes.

•  Bierhausa.Etal.MethilglioxalmodificationofNac1.8facilitatesnociceptiveneuronfiringandcauseshiperalgesiaindiabetesneuropathy.Nat.Med.2012;16:926-933.

PatologíasmasfrecuentesyTratamientosaplicadosenUTD Neuralgias Craneofaciales __________________________________________________________________

•  NeuralgiadelTrigémino•  NeuralgiadelGlosofaringeo•  NeuralgiaOccipital•  ClusterHeadache,etc

•  Fármacos•  Anticonvulsivantes:

•  Carbamacepina•  Oxcarbamacepina•  Lamotrigina•  Gabapentina

•  AntidepresivosTricíclicos•  RelajantesMusculares:Baclofen,Tizanidine

•  Fisioterapia(EM),TtoPsicológico•  TratamientoQuirúrgico:

•  DescompresiónMicrovascular•  RadiocirugíaconGammaKnife•  TratamientoPercutáneo⇒LesiónporRadiofrecuencia⇒UnidadesdeTratamientodeDolor

Radiofrecuenciatérmicaesunprocedimientoenelqueseutilizaunelectrodoparaenviarunacorrientealternaquecirculaentrelapuntadelelectrodoyunaplacadedispersión,generandounafriccióniónicaquealcanzaunatemperatura80-85°alrededordelapuntadelelectrodo,situadoadyacentealnervio,conelobjetivodeproducirunacoagulación,queinterrumpalaconducciónatravésdelmismoSifraccionamoslacorrienteenintervalosylaTªesmenora65°Cnocoagula,nolesiona⇒generauncampoeléctricoquealteralaconducciónA𝛿yC⇒pRF

Radiofrecuencia en el Ganglio de Gasser

Tratamiento de la NPH _____________________________________ •  Prevención:Vacunaenpacientes>60a.•  Fármacosdeelecciónendolorneuropático

•  Antidepresivostricíclicos•  Gabapentina,Pregabalina•  Tratamientostópicos:ParchedeLidocaína,ParchedeCapsaicinacada3meses

•  Fármacosdeterceraelección •  Opioidesduales:Tapentadol

•  Tratamientosintervencionistas•  GanglioRaízDorsal•  Neuroestimulaciónperiféricasubcutánea•  NeuroestimulaciónenelDRG

•  Psicológico

Otros Tratamientos Simpatectomía Lumbar

Radiofrecuencia Epidural

Pancreatitis crónica Radiofrecuencia sobre Nervios Esplácnicos

Bloqueo de Plexo Celíaco

Bloqueo de Plexo Hipogástrico Ganglio Walter

Tratamientos con Capsaicina

Perspectivas _________________________________________

•  LospacientesconDNtienencalidaddevidadisminuida⇒SF36muchomasbajosDN⇒las

puntuacionesde8parámetros:Vitalidad,formafísica,dolorcorporal,percepcióndesalud,

funcionamientofísico,funciónemocional,funciónsocialysaludmental,estándisminuidas

•  DeterminarlosFenotipos,esdegranimportancia.•  Cualquiertratamientopersonalizadodeldolorsebasaráenlacapacidaddeseleccionarlospacientesquepuedanresponder.DorkinRH.Pain2014;155:457-460

•  Pacientescon2Fenotiposdominantes⇒Alodiniamecánicayfunciónnociceptivapreservadapuedenresponderalosbloqueadoressistémicosytópicosdelcanaldesodio.

•  Pacientesconperfilexcitatorio⇒respondenmejoralosantiepilépticos•  LosestudiosgenéticosdemuestranqueelNav1.7esunobjetivocrucialparatratareldolor

Perspectiva

1.  DISEÑODEENSAYOSCLÍNICOS

2.  DETERMINARADECUADAMENTELOSFENOTIPOS

3.  TRATAMIENTOPERSONALIZADODELDOLOR

4.  RESPONDERMEJORALASEXPECTATIVASDELPACIENTE.

Moltes Gracies