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1 GRÜNENTHAL Name der Präsentation Datum Page 1

2 Cenni di Neurofisiologia del Dolore Neuropatico Localizzato e Linee Guida di Trattamento Roberto Casale, MD, PhD Montescano EFIC School, Director Foundation Salvatore Maugeri IRCCS Scientific Institute of Montescano Dept. of Clinical Neurophysiology & Pain Rehabilitation Unit Montescano (PV) Italy GRÜNENTHAL Name der Präsentation Datum Page 2

4 Condition Diabetic NP PHN Level A rating of evidence Duloxetine Gabapentin-morphine TCA Gabapentin Oxycodone Pregabalin TCA Tramadol alone or with Paracetamol Venlafaxine ER Capsaicin 8% patch* Gabapentin Gabapentin ER Lidocaine patch Opioids Pregabalin TCA a EFNS guidelines Level B rating of evidence BTX-A** Dextromethorphan Gabapentin/ Venlafaxine** Levodopa** Capsaicin cream Valproate** Recommendations for first line Duloxetine Gabapentin Pregabalin TCA Venlafaxine ER Gabapentin Pregabalin TCA Lidocaine patch Classic TN Carbamazepine Oxcarbazepine Carbamazepine Oxcarbazepine Central pain Cannabinoids (oro-mucosal* oral) (MS) Pregabalin (SCI) Lamotrigine (CPSP) TCA (SCI, CPSP) Tramadol (SCI)** Opioids Gabapentin Pregabalin TCA Recommendations for second line Opioids Tramadol Capsaicin Opioids Surgery Cannabinoids (MS) Lamotrigine Opioids Tramadol (SCI) Attal et al., Eur J Neurol 2010 GRÜNENTHAL Name der Präsentation Datum Page 4

5 Botulinum toxin Painful neuropathies Ranoux et al., Ann Neurol 2008 GRÜNENTHAL Name der Präsentation Datum Page 5

6 1st and 2nd Line Recommendations L ordine di scelta deve tener conto di altri fattori che non siano solo la bontà degli RCT e quindi non basta il livello di evidenza, anche se la scelta va fatta sempre all interno delle terapie sostenute da adeguata evidenza. Bisogna tener conto dell efficacia (da non confondere con il livello di evidenza), della tollerabilità e degli effetti sulla qualità di vita, della sicurezza (da non confondersi con la tollerabilità). Il tutto, però, sempre a livello di indicazioni/norme generali applicabili alla maggioranza della popolazione. G.Cruccu, Position Meeting, Roma 2013 GRÜNENTHAL Name der Präsentation Datum Page 6

7 Number needed to treat (NNT) and Number needed to harm (NNH) Finnerup et al. Pain 2010 GRÜNENTHAL Name der Präsentation Datum Page 7

8 Importance of QoL and comorbidities In the majority of pain trials, pain relief is the primary endpoint In clinical practice, our goal is to provide the patient with a good standard of living Hence, the evaluation of treatments for their effect on global change, sleep, mood, functional capacity, and QoL are recommended 1 QoL=Quality of life. 1. Attal N, et al. Eur J Neurol GRÜNENTHAL Name der Präsentation Datum Page 8

9 Major discussions: safety concerns about opioids The lack of long-term studies of opioids in chronic non-cancer patients pain was one of the main objections raised in the guidelines 1 We believe that in patients with non-cancer pain the long span of life may pose unknown problems with opioid treatments However, the discussion is still open. More controlled, long-term studies, and QoL assessments are needed 1 1. Attal N, et al. Eur J Neurol. 2010; 2. Portenoy RK, et al. Clin J Pain GRÜNENTHAL Name der Präsentation Datum Page 9

10 Recommendations from EFNS guidelines Condition Level A rating for efficacy Level B rating for efficacy Recommendations for first line Recommendations for second line Diabetic NP Duloxetine Gabapentin-morphine TCA, Gabapentin Oxycodone Pregabalin, TCA Tramadol alone or with Paracetamol Venlafaxine ER BTX-A** Dextromethorphan Gabapentin/ Venlafaxine** Levodopa** Duloxetine Gabapentin Pregabalin TCA Venlafaxine ER Opioids Tramadol PHN Capsaicin 8% patch* Gabapentin Gabapentin ER Lidocaine patch Opioids Pregabalin, TCA a Capsaicin cream Valproate** Gabapentin Pregabalin TCA Lidocaine 5% patch Capsaicin Opioids Classic TN Carbamazepine Oxcarbazepine Carbamazepine Oxcarbazepine Central pain Cannabinoids (oro-mucosal* oral) (MS) Pregabalin (SCI) Lamotrigine (CPSP) TCA (SCI, CPSP) Tramadol (SCI)** Opioids Gabapentin Pregabalin TCA Surgery Cannabinoids (MS) Lamotrigine Opioids Tramadol (SCI) GRÜNENTHAL Name der Präsentation Datum Page 10

11 NeuPSIG Topical lidocaine: for patients with localized peripheral NP: topical lidocaine used alone or in combination GRÜNENTHAL Name der Präsentation Datum Page 11

13 Treatment algorithm 2011 Trig. Neuralgia Peripheral NeuP SCI CBZ/OXC Surgery Allodynia/pain in small area Lidocaine Pregabalin MS Cannabinoids Pregabalin 300 Duloxetine 60 CPSP? PGB 600 / AMI 75 / TAP 200 OXY 40 + NAL 20 Amitriptyline / MCS FBSS/CRPS Whenever sound evidence is unavailable try blue drugs first Spinal cord stimulation GRÜNENTHAL Name der Präsentation Datum Page 13

14 Linee guida per il trattamento del dolore neuropatico: strumento indispensabile ma prima è necessaria una diagnosi corretta GRÜNENTHAL Name der Präsentation Datum Page 14

15 Pain: Definition Pain, according to the International Association for the Study of Pain (IASP) An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage 1 Pain as disease Chronic pain is not simply acute pain that lasts longer. It is a disease process with different mechanisms 2 Understanding of the mechanisms or pathophysiology of chronic pain can guide optimal treatment 3 1- Merskey H, et al. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. 1994: Woolf CJ. Ann Intern Med. 2004;140: Baron R. Nat Clin Pract Neurol. 2006;2: GRÜNENTHAL Name der Präsentation Datum Page 15

16 IASP Definitions 1994/2008 Nociception: the neural processes of encoding and processing noxious stimuli Nociceptive stimulus: an actually or potentially tissue-damaging event transduced and encoded by nociceptors Dysesthesia: an unpleasant abnormal sensation, whether spontaneous or evoked Paresthesia: an abnormal sensation, whether spontaneous or evoked Hyperalgesia: increased pain sensitivity. Allodynia: pain in response to a non-nociceptive stimulus. Hyperpathia: a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a ripetitive stimulus, as well as an increased threshold GRÜNENTHAL Name der Präsentation Datum Page 16

18 Current IASP definition of neuropathic pain Neuropathic pain: Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system. Merskey & Bogduk 1994 Two problems: 1. Dysfunction physiological neuroplasticity?? 2. Pains secondary to a lesion GRÜNENTHAL Name der Präsentation Datum Page 18

19 Novel definition of neuropathic pain, accepted by the IASP Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Treede et al., Neurology, 2008 GRÜNENTHAL Name der Präsentation Datum Page 19

20 NeP diagnostic work-up algorithm with 3 levels of diagnostic certainty (somatic not visceral pain, no pain descriptors!) Pain part of the problem? Treede et al., Neurology, 2008 GRÜNENTHAL Name der Präsentation Datum Page 20

21 Definite: all 1 to 4 Probable: 1 and 2 plus either 3 or 4 Possible: 1 and 2 without conf. evidence from 3 or 4 GRÜNENTHAL Name der Präsentation Datum Page 21

22 Classificazione clinica del dolore neuropatico (DN) Dolore Neuropatico DN definito DN possibile DN improbabile Dolore in un'area neurologica definita Disturbo sensitivo nell'area dolorosa Malattia che causa lesione del nervo Lesione neurogena molto definita Dolore in un'area neurologica plausibile Disturbo sensitivo nell'area dolorosa Eziologia ignota Malattia causa di dolore nocicettivo Dolore in area non riferibile ad alcun tipo di innervazione Malattia causa di dolore nocicettivo Nessun disturbo sensitivo GRÜNENTHAL Name der Präsentation Datum Page 22

23 Classificazione del dolore neuropatico per eziologia e sede anatomica (Jensen, 2002, Eur J Pain) S. N. Periferico Midollo Spinale Aree cerebrali neuropatie sclerosi multipla siringobulbia lesioni traumatiche lesioni midollari ictus cerebri compressione mielopatie sclerosi multipla poliradicolite siringomielia PHN cordotomia HIV GRÜNENTHAL Name der Präsentation Datum Page 23

24 Classificazione clinica basata sui sintomi della sensibilità somatica Dolore neuropatico Spontaneo Evocato Continuo Parossistico Stimoli non nocicettivi (Allodinia) Stimoli nocicettivi (Iperalgesia) Meccanico Termico Meccanico Termico Freddo Caldo Freddo Caldo Allodinia meccanica Allodinia fredda Allodinia calda Iperalgesia meccanica Iperalgesia fredda Iperalgesia calda GRÜNENTHAL Name der Präsentation Datum Page 24

26 Any help from questionnaires for NeP? - The clinical usefulness of distinguishing features of NeP is related to their applicability in differential diagnostic issues. - A comprehensive background is available in each patient; history, pain drawing, pain characteristics, signsmake use of it! - Admittedly, sometimes we need more since no gold standard for the pain identification. GRÜNENTHAL Name der Präsentation Datum Page 26

27 Questionnaires for NeP identification - LBP (mixed without and with painful radiculopathy (10-20%)) and osteoarthritis have been studied and compared with PHN and DPN (Dworkin et al. 2007). - DN4 (Bouhassira et al. 2005) etc. - SLANSS (Bennett et al. 2005) GRÜNENTHAL Name der Präsentation Datum Page 27

28 Our results indicate that a comprehensive assessment of pain symptoms, which adjusts for overall pain intensity and unpleasantness, is likely to be an important component of the identification of pain mechanisms. No pathognomonic symptom! Dworkin et al GRÜNENTHAL Name der Präsentation Datum Page 28

29 Our results indicate that a comprehensive assessment of pain symptoms, which adjusts for overall pain intensity and unpleasantness, is likely to be an important component of the identification of pain mechanisms. No pathognomonic symptom! Dworkin et al GRÜNENTHAL Name der Präsentation Datum Page 29

30 Epidemiology of neuropathic pain based on questionnaires is a mess! Prevalence of 3-18 %!! Toth et al GRÜNENTHAL Name der Präsentation Datum Page 30

31 5 up to 12 Bennett et al GRÜNENTHAL Name der Präsentation Datum Page 31

32 INTERVIEW first EXAMINATION second Bouhassira et al GRÜNENTHAL Name der Präsentation Datum Page 32

33 Pressing issue! Learn more about neuropathic pain characteristics to pinpoint the neuropathic nature of pain in an area of neuropathy P. Hansson, Montescano EFIC School, GRÜNENTHAL Name der Präsentation Datum Page 33

34 .with a focus on somatosensory exam since pain is part of the somatosensory system. Hansson et al. 2001;Cruccu et al GRÜNENTHAL Name der Präsentation Datum Page 34

35 Bedside examination of sensibility Brush/tuning fork- A-beta Cold (A-delta) and warm (C) metallic rollers- the Lindblom rollers Pin (A-delta/C) Outline spatial extension!!-neuroanatomy? Outline abnormality profile GRÜNENTHAL Name der Präsentation Datum Page 35

37 Sensory abnormalities in neuropathy/neuropathic pain-what to expect Touch, pressure and cold Hansson 1994 GRÜNENTHAL Name der Präsentation Datum Page 37

39 Localized neuropathic pain: a definition Localized neuropathic pain is a type of neuropathic pain that is characterized by consistent and circumscribed area or areas of pain Mick G. Baron R., Finnerup N., et al. Pain Manage (2012); 2: GRÜNENTHAL Name der Präsentation Datum Page 39

40 Come fare diagnosi di Localized Neuropathic Pain Roberto Casale, MD, PhD Montescano EFIC School, Director Foundation Salvatore Maugeri IRCCS Scientific Institute of Montescano Dept. of Clinical Neurophysiology & Pain Rehabilitation Unit Montescano (PV) Italy GRÜNENTHAL Name der Präsentation Datum Page 40

41 Linee guida per il trattamento del dolore neuropatico: strumento indispensabile ma prima è necessario una diagnosi corretta di NP e ancora più corretta di LNP GRÜNENTHAL Name der Präsentation Datum Page 41

43 Localized neuropathic pain: una definizione condivisa Un tipo di dolore neuropatico caratterizzato da una o più aree costanti e circoscritte di massimo dolore, associate a segni sensoriali negativi o positivi e/o sintomi spontanei caratteristici del dolore neuropatico Mick G., Baron R., Finnerup N., et al. Pain Manage (2012); 2: GRÜNENTHAL Name der Präsentation Datum Page 43

44 Excuse me please, where the pain is! GRÜNENTHAL Name der Präsentation Datum Page 44

45 Ranoux et al., Ann Neurol 2008 GRÜNENTHAL Name der Präsentation Datum Page 45 Botulinum toxin Painful neuropathies

46 Get lost? Get a map!! GRÜNENTHAL Name der Präsentation Datum Page 46

48 Referred myofascial pain Dong Hwee Kim Intramuscular Hemangioma Mimicking Myofascial Pain Syndrome : A Case Report J Korean Med Sci Jun;22(3): GRÜNENTHAL Name der Präsentation Datum Page 48

49 Drewes et al. Multimodal pain stimulations in patients with grade B oesophagitisgut 2006;55: GRÜNENTHAL Name der Präsentation Datum Page 49

52 I pazienti con NP e in particolare con PHN spesso sperimentano più di un tipo di dolore Bruciante Dolente Lancinante Intorpidimento Tagliente A scariche Irritante Fino al 90% dei pazienti con PHN presenta allodinia [1] Adapted from Davies PS and Galer BS. Drugs. 2004; 64: GRÜNENTHAL Name der Präsentation Datum Page 52

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54 Quali sono i meccanismi fisiopatogenetici del dolore cronico neuropatico localizzato LNP GRÜNENTHAL Name der Präsentation Datum Page 54

55 Peripheral Central Major anatomical site of lesions GRÜNENTHAL Name der Präsentation Datum Page 55

56 Dolore somatico superficiale Dolore somatico profondo/viscerale GRÜNENTHAL Name der Präsentation Datum Page 56

57 CNS modifications temporal cascade following a lesion or a neurogenic inflammation AMPA NMDA WIND-UP/WDR NEURONE SENSITIZATION SP CGRP NKA VIP Ca 2+ NO PKC PG Na sympathetic sprouting c-fos dynorphin neuropeptide Y galanin colecystokinin growt factor cell death dorsal horn remodelling 1ms 10ms 100ms sec minutes hours days weeks months years AMPA receptors NMDA receptors SP Substance P CGRP Colecistokinin Gene Related Peptide PG Prostaglandin NO Nitric Oxide PKC Protein Kinase C VIP Vasoactive Intestinal Peptide GRÜNENTHAL Name der Präsentation Datum Page 57

58 Diversi livelli di danno e riorganizzazione del network nocicettivo EVENTI CENTRALI riorganizzazione anatomica delle lamine dorsali: aumento attività spontanea di scarica neuroni DRG, ridotta soglia d attivazione, aumento campi recettivi (iperalgesia secondaria?) aumento compensatorio attività pre- e post-sinaptica selettiva per canali calcio-attivati di tipo N modificazioni recettori NMDA, plasticità GRÜNENTHAL Name der Präsentation Datum Page 58

59 Diversi livelli di danno e riorganizzazione del network nocicettivo EVENTI PERIFERICI alterazioni morfologiche: perdita di fibre C e redistribuzione locale di fibre mieliniche che invadono i territori di pertinenza delle terminazioni libere (allodinia?) alterazioni molecolari: riorganizzazione canali sodio per distribuzione e densità, con conseguente aumento attività spontanea sodio-dipendente ; modificazioni recettoriali plasticità periferica campo recettoriale GRÜNENTHAL Name der Präsentation Datum Page 59

60 Canali del sodio permettono l ingresso di ioni sodio (Na+) all interno delle cellule su cui sono presenti, ossia su tutte le cellule eccitabili; sono molto numerosi a livello del cono d emergenza dell assone nei motoneuroni, ove generano il potenziale d azione, e a livello dei nodi di Ranvier per la progressione dell impulso lungo le fibre nervose. GRÜNENTHAL Name der Präsentation Datum Page 60

62 Peripheral nerve injury leads to ectopic discharges initiated at the site of injury. These discharges are thought to cause peripheral and spinal sensitization Neurotrophic factors as novel therapeutics for neuropathic pain Dinah W.Y. Sah, Michael H. Ossipo & Frank Porreca Nature Reviews Drug Discovery 2, (June 2003) GRÜNENTHAL Name der Präsentation Datum Page 62

63 The expansion of the receptive field GRÜNENTHAL Name der Präsentation Datum Page 63

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65 Neuroma: chemical, mechanical, electrical hypersensitivity Spreading cellular pathobiology involved in cell death, regeneration and pain following peripheral nerve transection. The sequence of events should start at proximal sprouts of neuroma (right side) and then move to dorsal root (DR) ganglion neuron to postsynaptic spinal cord neuron. From data by Herdegen, Gillardon and Zimmermann GRÜNENTHAL Name der Präsentation Datum Page 65

66 Even if an ectopical and spontaneous raise of nerve discharge can occur in the proximal part of the injred nerve, it is reasonable to support the idea that a neuroma becomes painful under for instance a continuous stimulation. It is worth of note that C fibers are less prone to spontaneous discharge than A-beta fibers. GRÜNENTHAL Name der Präsentation Datum Page 66

67 Ipereccitabilità neuronale nella neuroprassia: after discharge Nella lesione nervosa con conservazione dell assone e danno alla mielina, si possono generare impulsi nella sede di lesione mielica con scarica sia spontanea che a seguito di stimolazione lesionale Quando la scarica ectopica è provocata questa può essere provocata sia da uno stimolo sulla lesione che da un attivazione fisiologica dell assone. Si tratta quindi prevalentemente un meccanismo a carico delle fibre mielinizzate (allodinia). Il meccanismo è detto di after discharge o moltiplicazione degli impulsi GRÜNENTHAL Name der Präsentation Datum Page 67

68 Cross-excitation/talking Chemical crosstalking Ephaptic crosstalking Crossed afterdischarge Name der Präsentation Datum Page 68

69 Chemical crosstalking Avviene quando una fibra lesa viene attivata dal rilascio di ioni da una fibra vicina integra. GRÜNENTHAL Name der Präsentation Datum Page 69

70 Electric crosstalking When the myelin sheath is damaged, (i) a spike propagating in one axon can induce (ii) a depolarization in the other axon, which might lead to (iii) the generation of a full spike. The two best-known types of cell cell communication are chemical synapse and electrical synapses, which are formed by gap junctions. A third, less well known, form of communication is ephaptic transmission, in which electric fields generated by a specific neuron alter the excitability of neighboring neurons as a result of their anatomical and electrical proximity. Ephaptic communication can be present in a variety of forms, each with their specific features and functional implications. In pathological situations where the myelin sheath of neurons is damaged, a neuron can affect its neighbors by spreading current through the extracellular space. Thus, a spike generated in one axon induces a small potential difference in a neighboring axon, which could lead to the generation of a spike that couples the two axons (a). It was erroneously believed that this type of ephaptic communication only occurred in pathological conditions such as neuropathic pain GRÜNENTHAL Name der Präsentation Datum Page 70

71 Paroxysmal afterdischarge due to direct mechanical stimulation of a DRG and to DRG cross-excitation afterdischarge. The sciatic nerve is partially injured. A gentle rubbing of the skin of the hind paw evoked a crossed afterdischarge burst. The recorded neuron did not respond directly to the skin stimulus as its axon had been cut across before placement on the recording electrode (R). However, neighboring neurons in the DRG with intact axons were directly activated and their activity cross-excited the recorded neuron. GRÜNENTHAL Name der Präsentation Datum Page 71

72 100 Pain threshold HYPERALGESIA Pain intensity Acute physiological pain ALLODYNIA Stimulation intensity GRÜNENTHAL Name der Präsentation Datum Page 72

73 Trattamento del dolore neuropatico localizzato Roberto Casale, MD, PhD Montescano EFIC School, Director Foundation Salvatore Maugeri IRCCS Scientific Institute of Montescano Dept. of Clinical Neurophysiology & Pain Rehabilitation Unit Montescano (PV) Italy GRÜNENTHAL Name der Präsentation Datum Page 73

74 Sensibilizzazione periferica SNP Na + CBZ OXC Fenitoina TPM LTG Lidocaina Mexiletina TCA Midollo spinale Modulatori della sensibilizzazione periferica GRÜNENTHAL Name der Präsentation Datum Page 74

75 Sistema inibitorio discendente Cervello SNP NA/5HT Recettori oppioidi Sensibilizzazione periferica Na + CBZ OXC Fenitoina TPM LTG Lidocaina Mexiletina TCA Midollo spinale TCA SSRI SNRI Tramadolo Oppiacei Calcio: NMDA: Sensibilizzazione centrale Altri Capsaicina Levodopa FANS Coxib GBP, LVT, OXC, LTG Ketamina Destrometorfano Memantina Metadone GRÜNENTHAL Name der Präsentation Datum Page 75

77 Linee guida EFNS (Attal N et al. Eur J Neurol 2010) Raccomandazioni per il trattamento farmacologico di prima, seconda e terza linea nella PHN Raccomandazioni per la prima linea Raccomandazioni per la seconda o terza linea Livello A per efficacia Livello B per efficacia Llivello A/B per inefficacia o risultati discordanti Gabapentin Pregabalin TCA Lidocaina cerotto 5% 1 Capsaicina Oppioidi Cerotti con capsaicina 8% Gabapentin Gabapentin RP** Lidocaina cerotto 5% Oppioidi 2 Pregabalin TCA 3 Capsaicina in crema Valproato* Benzidamide topico Destrometorfano Flufenazina Memantina Lorazepam Mexiletina Inibitori della COX- 2** Tramadolo Sono stati riportati solo i farmaci a dosaggi ripetuti (a eccezione dei trattamenti con effetti prolungati come i cerotti con capsaicina). 1 Lidocaina raccomandata specialmente in pazienti anziani; 2 Morfina, ossicodone, metadone; 3 Amitriptilina, nortriptilina, desipramina, imipramina. * Risultato efficace in studi singoli di classe II o III e generalmente non raccomandato; PHN = Nevralgia post-erpetica; TCA = Antidepressivi triciclici; RP = rilascio prolungato GRÜNENTHAL Name der Präsentation Datum Page 77

78 Nevralgia post-erpetica (PHN) Conseguenze cliniche e tipo di dolore I pazienti con PHN spesso sperimentano più di un tipo di dolore Bruciante Dolente Lancinante Intorpidimento Tagliente A scariche Irritante Fino al 90% dei pazienti con PHN presenta allodinia [1] Adapted from Davies PS and Galer BS. Drugs. 2004; 64: QoL Depressione GRÜNENTHAL Name der Präsentation Datum Page 78

79 Postherpetic neuralgia can occur due to nerve damage (FDA) Superficial pain Localized pain Burning sensation Name der Präsentation Datum Page 79

80 Basta con il dolore inutile Name der Präsentation Datum Page 80

81 Il comportamento doloroso: l homme douleurox Name der Präsentation Datum Page 81

82 Dolore cronico come moltiplicatore di malattia Name der Präsentation Datum Page 82

83 Qualità della vita Name der Präsentation Datum Page 83