“Controversie sulla diagnosi
e terapia del dolore neuropatico”
Opinioni a confronto
Gli oppioidi sono indicati nel
dolore neuropatico? NO
Marco Lacerenza
Medicina del Dolore
Fondazione “Opera San Camillo”
Casa di Cura S. Pio X, Milano
Palermo, 29-30 novembre 2012, Reale Albergo delle Povere
O meglio….ATTENZIONE!
Premessa
RCT, Linee Guida…………..artefatti della medicina
moderna che danno DATI UTILISSIMI MA………….
Possono subire le influenze di forze non utili al nostro fine
Possono facilitare le generalizzazioni
possono facilitare la medicina della INDICAZIONE senza valutazione
sedano l’ansia del giovane medico e accorciano le visite dell’esperto
Proteggono dal pdv medico legale
Smettiamola di parlare di “Dolore Neuropatico”
Parliamo di Pazienti SOFFERENTI, con dolore spesso
neuropatico, cronico, complessi, con molte comorbidità
Ognuno diverso dall’altro, con scarsa QoL e problemi
famigliari, lavorativi, economici
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
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 by introducing variability of
the MOR responsiveness to exogenous opioids.
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
I recettori per gli oppioidi
I recettori per gli oppioidi: binding
Perché funzionano poco????
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 .
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
Genetic mechanisms
Sensitiz. of primary afferent N.
Central Glutamatergic system
Descending facilitation (in
RVM on-cells and CCK) leading
to up-regulation of Spinal
dynorphin and enhanced primary
afferent neurotransmitter release
(CGRP) and pain.
Decreased reuptake of
neurotransmitters from the
primary afferent fibers
Pain that has become more diffuse and less
defined in quality and has a wider spatial
distribution than the pre-existing pain.
NMDA receptors become activated and when
inhibited, prevent the development of tolerance
and OIH
The glutamate transporter system is inhibited,
(increasing the amount of glutamate available to NMDAR)
Ca regulated intracellular PKC is likely a link
between cellular mechanisms of tolerance and
OIH
Prolonged morphine administration induces
neurotoxicity via NMDA receptor mediated
apoptotic cell death in the dorsal horn
Smith HS, 2012
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), 2009
Eisenberg E, McNicol ED, Carr DB
Short-term studies: equivocal evidence regarding the efficacy of
opioids in neuropathic pain.
Intermediate-term studies demonstrated significant efficacy of opioids
over placebo for neuropathic pain.
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.
…the participants in the included studies may not reflect those
commonly seen in practice. Therefore, issues such as abuse of
medication, or conversely, non-compliance due to participants’
unwillingness to tolerate side effects may not be accurately reflected in
our results.
 Studi epidemiologici documentano nel LBP
dolore misto nel 20-35% dei casi
 1/3 della popolazione ha LBP, quindi il 6% ha
una componente neuropatica
 Il costo dei pazienti con LBP e componente
neuropatica è il 70% > rispetto a LBP nocicettivo
The meta-analysis of Martell et al. 2007 identifies
also a number of relevant issues:
patients were more likely to be prescribed opioids if
they reported greater distress and suffering.
The prevalence of substance abuse disorders was in
the range of 40% to 50% in these patients and up to
24% showed aberrant medication-taking behaviour
Long-term trials of opioid efficacy for chronic
back pain are lacking, and there is other evidence
that indicates that the long-term efficacy of
opioids for chronic pain may be limited
Opioids and opioid combinations were exceeding NSAIDs in
proportion of patients and number of prescriptions.
Short-acting opioids are frequently used as rescue medication….
high prescribing..(36.5%). Although the frequency of use of longacting opioids was low (3.8%), the median (7.0) number of
prescriptions were higher than for any other medication.
Opioids continue to be recommended and used, despite evidence of a
negative association with outcomes in CLBP, including function and
productivity and an increased likelihood of substance use disorders.
In such “pathological pain states”, nociception is not the sole
target, but also suffering, dysfunction, mood states,
psychosocial factors and dependence on the health system.
Then opioid use is less likely to improve analgesia and even
less to yield psychological or functional improvement.
Several investigations have identified drug abuse in 18%
to 41% of patients receiving opioids for chronic pain.36-40
The prevalence of lifetime substance use disorders range
from 36% to 56%, with an estimate of 43% current
substance use disorders and 5% to 24% of the patients with
aberrant medication taking behaviours.
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
Unintentional overdose death
related to an opioid analgesic
9 persons are
admitted for
substance abuse
treatment
35 visit ER
161 report drug abuse or dependence
461 report nonmedical uses of opioid analgesics
It has been shown that from 1997 through 2007, there was a seven fold increase in
the number of prescriptions for opioids.
The pharmaceutical industry aggressively marketed long-acting opioids for chronic
pain relying on 2 erroneous facts:
That medical management with opioids is the recommended solution for
undertreated chronic pain
That the use of long-acting formulations decreases incidences of prescription
opioid abuse.
The principles of opioid management in acute pain and cancer pain were
transferred to the chronic pain arena.
JAMA 2000, 283: 1710-1714: ”Increased opioid use is not associated with
deleterious health consequences”.
Approximately two-thirds of the panel responsible for
writing guidelines for the use of opioids for chronic pain for
the American Academy of Pain Medicine (AAPM) and
American Pain Society (APS) had conflicts of interest with
the opioid pharmaceutical industry.
The investigation announced by the Senate in
reference to conflicts of interest in preparation of
opioid guidelines and promotion of opioid usage,
have resulted in abandonment of the American Pain
Foundation on May 10, 2012, which was a pivotal
organization in promoting opioid use.
Rischi del trattamento con oppioidi nel lungo termine:
Dipendenza fisica
Sviluppo di tolleranza
Iperalgesia indotta da oppioidi
Abuso e Dipendenza
Deficit cognitivi
Ipogonadismo (Disfunzioni sessuali, osteoporosi, depressione, fatica)
Alterazioni del sistema immunitario
(attraverso il sistema ipotalamo-ipofisi-surrene)
riduce la produzione di anticorpi
riduce l’attività delle cellule Natural Killer
riduce l’espressione di citochine
riduce l’attività fagocitaria
Opioid use for the management of pain in
fibromyalgia is strongly discouraged and is
not recommended by any current guideline.
1) women could be at higher risk for the negative medical
and psychological effects of opioids because they have
more persistent pain than men, and may be prescribed
opioids more often and at higher doses than men
2) multiple psychophysiological factors may contribute to
certain risks and consequences of chronic opioid
therapy
3) risks in pregnancy and breast-feeding
4) as in men, risks that are unique to women may increase
concomitantly with greater exposure to opioids (in
terms of frequency and dosage)
5) as in men, risks for women appear to vary at different
ages.
GRAZIE PER LA VOSTRA ATTENZIONE