Le lesioni periferiche nervose dell’arto superiore
LA TERAPIA NON INVASIVA
Dolore Neuropatico e
Oppioidi
Marco Lacerenza
Medicina del Dolore
Fondazione “Opera San Camillo”
Casa di Cura S. Pio X, Milano
21 novembre 2013, Peschiera del Garda
Dolore - Sofferenza
Sumeri: IX secolo AC: oppio
la pianta della gioia
Omero, IV libro Odissea
:….“Nel dolce Vino, di cui
bevean, farmaco infuse
contrario al pianto e all'ira, e
che l'obblìo seco inducea
d'ogni travaglio e cura”.
GaspareTraversi 1753
“Tra i rimedi che
Dio Onnipotente ha
voluto, bontà Sua, dare
all’uomo per alleviare
le sue sofferenze,
nessuno è universale
ed efficace come
l’oppio.”
Thomas Sydenham, 1624-1689
High
OPIOID RECEPTORS
ROLES IN VIVO
Distinct roles in hedonic
homeostasis and
emotional control
Mu
Delta
High
Modified from PE Lutz et al, 2013
Kappa
Mood
Low
Low
Individuals with high reward responsiveness, a personality trait
dependent on the endogenous opioid neurotransmission, experience
more exogenous opioid-induced behavioral analgesia.
Emerging evidence suggests that MOR polymorphism could contribute
to variability in behavioral opioid analgesia.
It is possible that trait RWR and the neuronal response to noxious stimuli
in the endogenous opioid-rich brain reward circuitry could be useful
endophenotypes of behavioral opioid analgesia.
Localizzazione dei
recettori per gli oppioidi
Corteccia cingolata anteriore,
C.prefrontale, strati superficiali
della corteccia cerebrale
Nuclei della base, talamo,
amigdala,
PAG, RMN, reticolare del tronco
Corno posteriore midollare:
– proiezioni midollari afferenti
primari
– Interneuroni midollari
Periferia: nocicettori e afferenti
viscerali
Oppioidi: Meccanismi d’azione
Legame Presinaptico
DRG
Blocco ingresso ioni Ca++
DNIC
Legame postsinaptico
Recettori
oppioidi
Fuoriuscita
ioni
Fuoriuscita didi
ioni
K+K+
Modificata da: A.H.Dickenson, 2000
Recettori per gli oppioidi e funzioni
βendorfine
Enkefaline
µ1
µ2
Dinorfine
κ
Enkefaline
βendorfine
δ
ζ
• Analgesia sovraspinale
• Euforia
•
•
•
•
Bradicardia
Depressione respiratoria
Sedazione
Dipendenza
•
•
•
•
Analgesia spinale e sovraspinale
Sedazione,
Disforia
Miosi
Analgesia spinale e sovraspinale
Disforia
Umore
• Opioid growth factor receptor
Dolore Neuropatico e Oppioidi
Smith HS, 2012
Perché funzionano meno nel dolore neuropatico????
Nerve-injury neuropathy and Diabetic Neuropathy:
Functional downregulation and/or desensitization
of μ-opioid receptors in the dorsal horn of the spinal cord
(but not a significant decrease in number) may be related to
increased production of PKC and/or mediated by PKA.
May be due to: activation of NMDARs in postsynaptic cells,
to an autophosphorylation of the TrkB receptor by BDNF.
In fact, the development of the hyperalgesia and allodynia in
NP states is suppressed by administration of NMDA receptor
antagonists, TrkB/Fc chimera protein (sequesters endogenous
BDNF), PKC inhibitors.
Dolore Neuropatico:
Meccanismi che portano
alla desensitizzazione di
MORs
Ridotta efficacia
nella pratica clinica
Dolore Neuropatico
Dolore
Spontaneo
Dolore
Provocato
Segno di Tinel, SLRT
bruciante,
lancinante,
Lhermitte, Spurling
rodente,
folgorante,
crampiforme, pugnalata
Allodinia Iperalgesia
sordo,
tagliente
Freddo
Meccanica
Meccanica
Caldo
Statica
Dinamica
Puntura
Caldo
Freddo
Dolore
Provocato
Segno di Tinel, SLRT
Lhermitte, Spurling
Allodinia
Meccanica
Dinamica
Meccanica
Statica
Caldo
Iperalgesia
Freddo
Caldo
Freddo
Puntura
Short-term studies opioids (alfentanyl and morphine) can
reduce the intensity of dynamic mechanical allodynia and
perhaps of cold allodynia in peripheral but not central NP.
Insufficient evidence precludes drawing conclusions
regarding the effect of opioids on other forms of evoked NP.
Metanalysis of intermediate-term studies (4W) demonstrates
efficacy of oxycodone over placebo for evoked NP.
Pain that has become more diffuse and less
Genetic mechanisms
defined in quality and has a wider spatial
Sensitiz. of primary afferent N.
distribution than the pre-existing pain.
Central Glutamatergic system
Descending facilitation (in
NMDA receptors become activated and when
RVM on-cells and CCK) leading inhibited, prevent the development of tolerance
and OIH
to up-regulation of Spinal
The glutamate transporter system is inhibited,
the amount of glutamate available to NMDAR)
dynorphin and enhanced primary (increasing
Ca regulated intracellular PKC is likely a link
afferent neurotransmitter release between cellular mechanisms of tolerance and
OIH
(CGRP) and pain.
Prolonged morphine administration induces
neurotoxicity via NMDA receptor mediated
Decreased reuptake of
apoptotic cell death in the dorsal horn
neurotransmitters from the
primary afferent fibers
Opioids have the potential to activate both pronociceptive
and antinociceptive pathways in a given individual
The effect of opioid treatment on DNIC in men seems to be
dose and time related, since both high opioid dose and long
treatment duration result in reduced magnitude of DNIC
Il risveglio americano dall’oppiofobia
“Opioid maintenance therapy can be a safe
salutary and more humane alternative…..in
those patients with intractable non-malignant
pain and non history of drug abuse”
The dichotomous classification of nociceptive and
neuropathic pain is not yet fully recognized in the pain
literature or among physicians dealing with pain.
..comon narcotic analgesics, administered in a double-blind
fashion and in doses which effectively control acute and
chronic nociceptive pain, are inefficient for relief of
neuropathic (including deafferentation) pain…..
The reason ………..is unknown.
Opioids for neuropathic pain (Review), 2013
McNicol ED, Midbari A, Eisenberg E
31 trials met our inclusion criteria, studying 10 different
opioids: 23 studies from the original 2006 review and 8
additional studies from this updated review.
Short-term studies: mixed results,with just over half indicating that
opioids might be better than a placebo.
Intermediate-term studies demonstrated significant efficacy of
opioids over placebo, but these results are likely to be subject to
significant bias because of small size, short duration, and potentially
inadequate handling of dropouts.
Analgesic efficacy of opioids in chronic neuropathic pain is subject to
considerable uncertainty.
The difference in outcomes does not support the use of short-term
opioid administration as a predictive tool to decide whether to initiate
intermediate-term opioid therapy.
Opioids for neuropathic pain (Review), 2013
McNicol ED, Midbari A, Eisenberg E
Short-term studies
Opioids for neuropathic pain (Review), 2013
McNicol ED, Midbari A, Eisenberg E
Intermediate-term studies
Opioids for neuropathic pain (Review), 2013
McNicol ED, Midbari A, Eisenberg E
Issues such as rare but serious adverse events, abuse of
medication, or conversely, non-compliance due to
participants’ unwillingness to tolerate side effects may not be
accurately reflected in our results.
Clinicians may be required to assess persons’ suitability for a
trial of opioid therapy and to monitor progress more
rigorously than they would for other pharmacological
treatments.
Linee guida & Revisioni EBM
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
BTX-A**
Dextromethorphan
Gabapentin/
Venlafaxine**
Levodopa**
Duloxetine
Gabapentin
Pregabalin
TCA
Venlafaxine ER
Opioids
Tramadol
Capsaicin cream
Valproate**
Gabapentin
Pregabalin
TCA
Lidocaine plasters
Capsaicin
Oxycodone
Pregabalin
TCA
Tramadol alone or with
Paracetamol
Venlafaxine ER
PHN
Capsaicin 8% patch*
Gabapentin
Gabapentin ER
Lidocaine plasters
Opioids
Opioids
Pregabalin
TCAa
Classic TN
Carbamazepine
Oxcarbazepine
Carbamazepine
Oxcarbazepine
Surgery
Central pain
Cannabinoids
(oro-mucosal* oral) (MS)
Pregabalin (SCI)
Lamotrigine (CPSP)
TCA (SCI, CPSP)
Gabapentin
Pregabalin
TCA
Cannabinoids (MS)
Lamotrigine
Tramadol (SCI)**
Opioids
Opioids
Tramadol (SCI)
Attal et al., Eur J Neurol 2010
Several RCTs have shown that opioid analgesics
provide greater pain relief than placebo in different
types of NP with analgesia at least as great as that
found with TCAs and gabapentin.
However, because of concerns regarding long-term
safety, including risks of hypogonadism,
immunologic changes, and opioid misuse or abuse,
opioids are not recommended for routine first-line
use and should generally be reserved for patients
who do not respond to the first-line medications.
Curr Med Res Opin. 2008 Dec;24(12):3503-12.
Cosa c’è di nuovo?
Safety and efficacy of tapentadol ER in patients with
painful diabetic peripheral neuropathy: results of a
randomized-withdrawal, placebo-controlled trial.
Tapentadolo ER (100–250 mg bid).
588 patients dolore cronico da almeno 3-mesi
stimato almeno 5 NRS, pazienti non soddisfatti
con il precedente trattamento.
Schwartz et al., Curr Med Res Opin 2011
Consigli pratici secondo linee guida 1
Stabilire una relazione medico paziente di fiducia reciproca
Porre l’indicazione in modo condiviso dopo aver escluso la
possibilità di altri trattamenti
Raccogliere informazioni sullo status psicosociale
RISCHIO DI DIPENDENZA e STATUS PSICO-SOCIALE
Fattori di Rischio per l’Abuso e la Dipendenza
Storia di abuso di sostanze
Disturbi mentali
Storia di dolori multipli
Genere maschile
Giovani adulti
Prescrizioni di > 90gg
ATTENZIONE
Programma multidisciplinare
Contratto
Spiegazioni esaustive dei rischi
a breve e lungo termine
Valutazione dolore, QoL, funzionamento
Supporto psicologico-occupazionale
Educativo-motivazionale
Fisioterapico
Consigli pratici secondo linee guida 1
Stabilire una relazione medico paziente di fiducia reciproca
Porre l’indicazione in modo condiviso dopo aver escluso la
possibilità di altri trattamenti
Raccogliere informazioni sullo status psicosociale
Sottolineare l’importanza del rendere il Paziente parte
attiva del trattamento condividendo obiettivi e rischi del
trattamento
Scegliere il farmaco pensando all’evoluzione di malattia
Evitare farmaci a breve emivita (ideali per ‘breakthrough pain’)
Preferire formulazioni a rilascio prolungato
Preferire agonisti puri
Consigli pratici secondo linee guida 2
Partire con dosaggio più basso ed incrementare lentamente
Accordarsi per strategie di uscita dalla terapia
Monitorare nel tempo il trattamento con scale
Coinvolgere il Paziente in Programmi Multidisciplinari
Monitorare i farmaci al bisogno e l’uso di psicofarmaci
Se compare tolleranza intensificare i controlli
Eventuale rotazione degli oppioidi
Combinazioni per ridurre i dosaggi e gli effetti collaterali
Evitare modifiche multiple alla terapia
Ridurre e sospendere i farmaci inutili
Ridurre e sospendere la terapia se benessere stabile
GRAZIE PER LA VOSTRA ATTENZIONE