Gli oppioidi sono indicati nel dolore neuropatico ? NO

1. “Controversie sulla diagnosi e terapia del dolore neuropatico” Opinioni a confronto Glioppioidisonoindicatineldoloreneuropatico? 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

2. 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

3. Dolore - Sofferenza “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 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

4. High OPIOID RECEPTORS ROLES IN VIVO Distinctroles in hedonichomeostasis and emotionalcontrol Mu Reward Delta Kappa Low Low High Mood

5. Individuals with high reward responsiveness, a personality trait dependent on the endogenous opioid neurotransmission, experience more exogenous opioid-induced behavioral analgesia. Emergingevidencesuggests 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.

6. 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

7. Legame Presinaptico Oppioidi: Meccanismi d’azione DRG Blocco ingresso ioni Ca++ DNIC Legamepostsinaptico Recettori oppioidi Fuoriuscita di ioni K+ Fuoriuscita di ioni K+ Modificata da: A.H.Dickenson, 2000

8. I recettori per glioppioidi

9. I recettori per glioppioidi: binding

10. Perché funzionano poco???? Nerve-injury neuropathy and Diabetic Neuropathy: Functionaldownregulation and/or desensitizationof 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.

11. Dolore Neuropatico: Meccanismi che portano alla desensitizzazione di MORs Ridotta efficacia nella pratica clinica

12. Genetic mechanisms • Sensitiz. ofprimaryafferent 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-existingpain. 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 Prolongedmorphineadministrationinducesneurotoxicityvia NMDA receptor mediated apoptotic cell death in the dorsal horn

13. Smith HS, 2012

14. Il risveglio americano dall’oppiofobia “Opioidmaintenancetherapy can be a safesalutary and more humanealternative…..in thosepatientswithintractablenon-malignantpain and non historyofdrugabuse”

15. The dichotomous classification of nociceptive and neuropathic pain is not yet fully recognized in the pain literature or among physicians dealing withpain. ..comonnarcoticanalgesics, 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 ………..isunknown.

16. 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.

17. 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

19. 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 aberrantmedication-takingbehaviour 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

20. 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 long-acting 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.

21. 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 functionalimprovement. 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 medicationtakingbehaviours.

22. 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 Valutazione dolore, QoL, funzionamento Supporto psicologico-occupazionale Educativo-motivazionale Fisioterapico Contratto Spiegazioni esaustive dei rischi A breve e lungo termine

26. 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

27. It has been shown that from 1997 through 2007, there was a seven fold increase in the number of prescriptions foropioids. The pharmaceuticalindustryaggressivelymarketed 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 chronicpain arena. JAMA 2000, 283: 1710-1714: ”Increasedopioid use is not associated with deleterious healthconsequences”.

28. Approximatelytwo-thirdsofthe 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 investigationannouncedby 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.

29. 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

31. Opioidusefor the management ofpain in fibromyalgiaisstronglydiscouraged and isnotrecommendedbyanycurrentguideline.

33. women couldbe at higherriskfor the negative medicaland psychologicaleffectsofopioidsbecausetheyhavemore persistentpainthanmen, and maybeprescribedopioidsmore often and at higherdosesthanmen multiple psychophysiologicalfactorsmaycontributetocertainrisks and consequencesofchronicopioidtherapy risksin pregnancy and breast-feeding asin men, risksthat are uniqueto women mayincreaseconcomitantlywithgreaterexposuretoopioids(in termsoffrequency and dosage) asin men, risksfor women appeartovary at differentages.

34. GRAZIE PER LA VOSTRA ATTENZIONE