1

Dolore e SM: dalla patogenesi al trattamento

C. SOLAROS.C. Neurologia Ospedale PA MiconeASL3 genovese Genova

Augustus Frederick d‘Este (1794-1848)

� 1822: sudden visualdisturbance (at the funeralof a close relative)

� 1827: Both legs paralyzed

� 1828: very violent pain...making water is attendedwith difficulty

� 1830: stool flowed from mewithout my having beenaware

� ...in my acts of connection a deficiency of a wholesomevigor

� 1843 numbness all down the back... giddiness... Total abruption of strength

2

Il dolore è una esperienza sensoriale ed emozionale spiacevole

associata ad un danno tessutale

Nocicezione: fenomeno sensoriale

Dolore: interpretazione emozionale e cognitiva dello stimolo

LimbicForebrain

Thalamus/Hypothalamus

Midbrain

Medulla

Spinal cord(C3 – C4)

Body

3

Frontal lobe,Limbic forebrain

Thalamus/Hypothalamus

Midbrain

Medulla

Spinal cord(C3 – C4)

S1/S2Cortex

4

CLASSIFICATION

Pain syndromes have been classified as:nociceptive neuropathic

psycogenic painIdiopathicMixed pain

DOLORE NOCICETTIVO

Risposta appropriata a stimoli dolorosi

Espressione della fisiologica attivazione dei nocicettori- intenso, continuo- spesso pulsante- ad andamento crescente - generalmente circoscritto ad aree anatomiche ben definite

5

DOLORE NEUROPATICO

• Fenomeno non appropriato, secondario a disfunzione o lesione nervosa: deriva dalla stimolazione diretta delle fibre nervose o da modificazioni sinaptiche di tipo eccitatorio

• E’ spontaneo ovvero insorge senza uno stimolo

• È ectopico, non è innescato da una scarica dei nocicettori (insorge in sede anomala)

Dolore spontaneo, indipendente da stimoli(Sintomi descritti dal paziente)

Sintomi del dolore neuropatico

dolore bruciante continuo

parossistico

urente

dolore intermittente lancinante, a fitta

dolore a scossa elettrica

alcune parestesie/disestesie

6

Iperalgesia

Una risposta dolorosa incrementata e

sproporzionata verso stimoli che sono di solito dolorosi

Allodinia

Una risposta dolorosa conseguente a stimoli di

solito non dolorosi

7

{

Frequenza

• Nevralgia trigeminale: 36 (2%)

• Lhermitte: 152 (9%)

• Dolore disestesico: 303 (18.1%)

• Rachialgia: 274 (16.4%)

• Spasmi tonici dolorosi: 184 (11%)

• Solaro et al 2005

8

Soggetti con almeno 1 sintomo doloroso:

717 (42.8%)

Soggeti che assumevano farmaci per il dolore: 157 (9.4%)

The aim of this study was to evaluate

the PREVALENCE OF PAIN in amulticenter study using a face-to-faceinterview conducted by an expertneurologist in MS and evaluating paincharacteristics using 2 specific painquestionnaires: DN4 and NPSI.

9

METHODS

Data were collected in a multicenter,

cross-sectional study involving 6 MS centers using a face-to-face structured questionnaire compiled by a neurologist.

The only exclusion criterion was the occurrence of a relapse in the month preceding the beginning of the study.

DN4 QUESTIONNAIRE

10

RESULTSCHARACTERISTICS MEAN / N°

SUBJECTS FemaleMale

1253835 (66,6%)418 (33,4%)

MEAN AGE 33.9 SD 10.8

MEAN DISEASE DURATION

11

RR 916 (73.1%)

SP 248 (19.8%)

PP 55 (4.4%)

MEAN EDSS SCORE 2

CHRONIC PAIN

�458/1253 pz declared to have chronic pain

�DN4< 4 285/458 pz (22.7 %)

�DN4> 4 173/458 pz (13.8%)

11

NPSI

12

NPSI

�Pz with DN4>4: mean 41 (range: 5 - 97)

�Pz with paroxysmal pain a median of 37.5(range: 5 – 87)

�Pz without paroxysmal pain : median of 40(range: 8 – 97)

�There was no significant difference between these patients (p = 0.33)

13

Periferici Nevralgia trigeminale

Centrali Disconessione

Danno diretto

Demielinizzazione

Percezione del dolore somatico

Disturbi cognitivi-depressivi

Patogenesi

Components of pain history

Somatic aspects• Onset• Location• Quality• Quantity• Duration• Aggravating/alleviating

factors

Psychological aspects• Mood• Cognitive• Coping styles• Beliefs on pain

Social aspects• Impact on relationship• Capacity for intimacy• Activities of daily living• Vocational• recreational

14

Dimensions of Chronic Pain

Loneliness Hostility

Social Factors

Anxiety Depression

Psychological Factors

Pathological Process

Physical Factors

Traditional vs. biopsychosocial models of pain

Traditional BiopsychosocialView of pain as an illness as an experience

Determinants Disease Biopsychosocial factors

Management Physician only Physician + patient

Role of patient Passive Active

Goal Pain relief Quality of life

Focus of attention Somatic complaints Patient’s beliefs

Osborne TL, Jensen MP, Ehde DM, Hanley MA, Kraft G: Psychosocial factors associated with pain intensity, pain-related interference, and psychologial functioning in

persons with multiple sclerosis and pain Pain 2007; 127: 52 - 62

15

• Sleep disturbance 71%• Fatigue 63%• Attentional deficit 39%• Depression 38%• Anxiety 26%• Anorexia 19%

Meyer A: Pain and sensory complaints in multiple sclerosis Eur J Neurol 2004; 11: 479–82

Co-morbidity of central pain in MS

Difficolta da parte del paziente a riferire la sintomatologia depressiva (aspetti culturali,

insight, sesso, eta)Difficolta da parte del medico (prevalenza

della malattia di base sugli aspetti psicologici, scarsita di risorse diagnostiche, difficolta delle gestione delle co-morbilita)

Problematiche diagnostiche

16

Pain in Individuals With Multiple Sclerosis, Knee P rosthesis, and Post-herpetic Neuralgia: Learning From Focus Gr oup

Patients’ ExperienceSaverino Alessia MD and Solaro Claudio MD

Original spontaneous descriptors, possibly pathology-specific, emerged in all groups not

included in the MGPQ and pointed out the need to use assessment tools based on people experience.

Clinical Journal of Pain May 2012 – Volume 28 – Issue 4 – p 300-308

PatientsLikeMe: Consumer Health Vocabulary as a Folksonomy

DOLORE DISESTESICO ARTI INFERIORIONGOING EXTREMITY PAIN(DYSESTHETIC EXTREMITY PAIN)

� Sindrome dolorosa piu comune

� Dolore subcontinuo, descritto come fastidio, sensazione di pesantezza o bruciore.

� Scarsa risposta alla terapia

� Associato a deficit sensitivo

17

PATOFISIOLOGIA

� Coinvolgimento della via dolorifica (talora difficile da evidenziare ma sempre presente)

� Associato a danno midollare

TERAPIA

� Terapia cognitiva� Risultati molto modesti, si usano gli antidepressivi

triciclici o gli antiepilettici di nuova generazione.

18

AE = adverse event; CNB = cannabinoid; GBP = gabapentin; LEV = levetiracetam; LMT = lamotrigine; PGB = pregabalin

Study (year) Design Medication No. of patients

Mean dose Efficacy

No. of patients with AE

Cianchetti et al. (1999)a

Open-label LMT 15400 mg/day 2/15 complete; 6/15

partial 0

Breur et al. (2007)Double-blind, crossover

LMT 12 400 mg/day No different vs placebo 1

Houtchens et al. (1997)

Open-label GBP 25600 mg/day 15/22 complete or

partial 11/22 (5 withdrawals)

Rossi et al. (2009) Single-blind LEV 12 vs 8 placebo3000 mg/day Significant difference

8/12 (1 withdrawal)

Solaro et al. (2009) Open-label PGB 16154 mg/day 9/16 complete

(3 withdrawals)

Svendsen et al. (2004)

Crossover CNB 2410 mg/day Significantly lower

pain during active tratment

23/24 (0 withdrawals)

Rog et al. (2005) Double-blind CNB 34vs 32 placebo9.6 spray dailyb Significan

differenceactive treatment vs placebo

30/34 (2 withdrawals)

Central neuropathic pain

� 1 open-label trial

� 1 double blind placebo controlled parallel

� 3 cross-over trials no head-to-head studies

� 4 medications have been used

� 145 patients studied

� outcome subjective pain relief scored with a VAS

� 1 parallel plus with-drawal phase

19

20

Central neuropathic pain

The accurancy in specifying the type of pain and outcome was uncoupled in only 2 out of 12 trials (Truini et al 2013)

Trigeminal Neuralgia

� most widely recognised neuropathic syndrome in MS� Prevalence: 2-4% of MS patients� paroxysmal episodic triggered facial pain occurs

trigeminal area; indistinguishable from idiopathic TN� Patients are younger; TN is more frequently bilateral

21

MS-plaques in trigeminus entry zone

TERAPIA

� Triciclici: amitriptilina

� Anticonvulsivi: carbamazepina, lamotrigina, gabapentin, pregabalin, levetiracetam

� Altri: baclofen, misoprostolo

� Rizotomia

22

{

The international Classification of

headache disorders

{

23

{

Painful trigeminal neuropathy

attributes to MS plaque

Table Studies of medications for trigeminal neuralgia in multiple sclerosis (MS)

Study (year) Medications No. of patients Mean dose Efficacy No. of patients with AE

Espir and Millac (1970) CBZ 5 760 mg/day 4/5 1

Solaro et al. (2000) LMT + GBP 5 170 mg + 780 mg/day 5/5 0

CBZ + GBP 6 400 + 800 mg/day 6/6 0

Lunardi et al. (1997) LMT 5 165 mg/day 5/5 NS

Leandri et al. (2000) LMT 18 170 mg/day 17/18 1

Khan et al. (1998) GBP 7 1400 mg/day 6/7 complete; 1/7 partialNS

Solaro et al. (1998) GBP 6 900 mg/day 5/6 0

Zvartau-Hind et al. (2000) TPM 6 100 mg bid 5/6 0

Solaro et al. (2001) TPM 2 200 mg/day 2/2 NS

Reder and Arnason (1995) Misoprostol 7 570 µg/day 4/7 complete; 2/7 partial 0

DMKG Study Group (2003) Misoprostola 18600 µg/day 14/18

4

Pfau et al. (2012) Misoprostol 3 1000 µg/day 3/3 0

Jorns et al. (2009) LEV 10 320 mg/day 4/10 3

AE = adverse evente; bid = twice daily; CBZ = carbamazepine; DMKG = German Migraine and Headche Society; GBP = gabapentin; LMT =lamotrigine; NS = not specified; TPM = topiramate; LEV = levetiracetam;

24

Trigeminal neuralgia

� All open-label design,

� 11 trials have been found

� 5 medications used, in 2 cases combination therapy has been used

� a total of 85 patients treated

� outcome subjective pain relief scored with a VAS

� To date, there has been no randomised trial specifically on treatment of TN.

25

SPASMI DOLOROSI NOTTURNI

� Sia in flessione che in estensione, spesso descritti come crampi, spesso scatenati dal movimento o da stimoli sensitivi; frequente insorgenza notturna; associati a spasticita

� Terapia: baclofen, gabapentin, tiagabina

26

Tonic spasms

� Symptoms: paroxysmal attacks of unilateral most often very painful tonic cramps of the extremities lasting only a few minutes, triggered by sudden movements, changes of position or hyperventilation.

Guillain et al, Annales de Médecine1918: Sur une forme anatomo-clinique spéciale de neuro-myéliteoptique nécrotique aigue avec crises toniques tetanoïdes

Matthews 1958: “subcortical seizures and tetanus of central origin”

T2-weighted MRI, a few days after onset of paroxysmal dystonia: well-differentiated, rounded bright signal involving lateral part of thalamus, posterior limb of internal capsule and internal part of lenticular nucleus. (B) Postgadolinium-enhanced, T1-weighted sequences: enhancement restricted to posterior limb of internal capsule and internal part of lenticular nucleus

Waubant E, Alizé P, Tourbah A, Agid YParoxysmal dystonia (tonic spasm) in multiple sclerosis. Neurology 2001;57:2320-2321

THERAPY

� Muscle relaxants such as baclofen or benzodiazepine are useful to relieve spasms

� Short course of steroids

� Gabapentin at low dosage is effective in 20 out 22 patients (Solaro et al Multiple Sclerosis 2000)

� Tiagabine (5-30 mg) is effective in 4 out 7 patients (Solaro et al JNNP 2004)

27

Anodal tDCS is able to modulate abnormal cortical excitability in the human cortex.

28

Rachialgie

� Correlata a posture anomale

� Trattata con I comuni analgesici

� 20% dei soggetti

� Caratteristiche analoghe allapopolazione generale

Pain: indirectly disease-related

�Spasticity

�Flexor spasms

�Contractures

� (Infections)

29

Pain: related to disability andtreatment

�Neck pain in wheelchair users

�Osteoporosis

�Peripheral nerve lesions

� (Injection sites)

Spasticity: treatment

Medtronic® Baclofen pump

30

31

Sample enrichment

• Selection criteria seek to increase proportion

of individuals in the sample who are likely

to respond to pharmacological treatment

• Sample selection procedures and limits on

the generalizability

• Cannabis study (Novotna EJN 2011)

32

FARMACI AD AZIONESINAPTICA

FARMACI ADAZIONE SULLA CONDUZIONE

NEURONE DITERZO ORDINE

NEURONE DIPRIMO ORDINE

MIDOLLO

FANS

NEURONE DISECONDO ORDINE

NOCICETTORE

Siti d’azione dei farmaci sulle vie di conduzione del massaggio nocicettivo

Raccolta anamnesticaEsame neurologico

Dolore SI

Classificazione del dolore(DN4)

Valutazione delle co-morbilità

TERAPIA

Valutazione ausilii

Trattamenti

Valutazione terapista del dolore

Terapia medica

Infusione intra-tecale

Stimolazione midollare

33