Chronic Pain After Surgery Molecules

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Chronic pain after surgery. More than just a nuisance?

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  • Chronic Pain After Surgery Molecules

    1. 1. Mick Serpell Senior Lecturer Post-op Pain & Molecules <ul><li>Drug developments </li></ul><ul><ul><li>algorithm </li></ul></ul><ul><ul><li>combinations </li></ul></ul><ul><ul><li>prevention? </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>
    2. 2. Combination Pain <ul><li> post-operative </li></ul><ul><li>PHN, PDN trauma O/A, Rh/A </li></ul><ul><li>neuropathic  ---------------------------  nociceptive </li></ul><ul><ul><ul><li>(mixed)‏ </li></ul></ul></ul>
    3. 3. Drug Developments <ul><ul><li>optimal drug strategy </li></ul></ul><ul><ul><li>drug combinations </li></ul></ul><ul><ul><li>drug prophylaxis </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>
    4. 4. WHO ladder - Nociceptive Pain <ul><li>Step 1 </li></ul><ul><ul><li>Paracetamol </li></ul></ul><ul><ul><li>NSAIDs or COX II? </li></ul></ul><ul><li>Step 2 </li></ul><ul><ul><li>codeine, dihydrocodeine, dextropropoxyphene, meptazinol </li></ul></ul><ul><ul><li>often as co-analgesics ie: co-codamol </li></ul></ul><ul><li>Step 2  3 Tramadol </li></ul><ul><li>Step 3 </li></ul><ul><ul><li>morphine, diamorphine, pethidine </li></ul></ul><ul><ul><li>methadone, fentanyl, buprenorphine </li></ul></ul><ul><ul><li>oxycodone, hydromorphone </li></ul></ul>
    5. 5. Neuropathic analgesics <ul><li>Adjuvants </li></ul><ul><ul><li>tricyclic antidepressants </li></ul></ul><ul><ul><li>anticonvulsants </li></ul></ul><ul><li>others </li></ul><ul><ul><li>opioids </li></ul></ul><ul><ul><li>sodium channel blockers </li></ul></ul><ul><ul><li>NMDA antagonists </li></ul></ul><ul><ul><li>capsaicin </li></ul></ul><ul><ul><li>cannabis </li></ul></ul>
    6. 6. NNT 0 2 4 6 8 10 12 Topiramate* Antidepressants, SSRI Capsaicin NMDA antagonists* Mexiletine* Antidepressants, SNRI Gabapentin/pregabalin Tramadol Opioids Carbamazepine/lamotrigine/ phenytoin Valproate Tricyclic antidepressants 397 109 83 389 120 420 1057 149 81 466 150 214 Peripheral neuropathic pain drugs: NNT Adapted from Finnerup et al. Pain 118 (2005) 289–305 Lidocaine plaster NNT to achieve pain relief >50%
    7. 7. Peripheral neuropathic pain drugs: NNH (withdrawal of Rx)‏ NNH 0 5 10 15 20 Antidepressants, SSRI Valproate Mexiletine Carbamazepine/lamotrigine/ phenytoin Gabapentin/pregabalin Opioids Antidepressants, SNRI Tricyclic antidepressants NMDA antagonists Capsaicin Tramadol Topiramate ns Finnerup et al. Pain 118 (2005) 289–305 Lidocaine plaster
    8. 8. Algorithm for neuropathic pain treatment: an evidence based proposal Lidocaine patch* TCA (SNRI)‏ Gabapentin/ Pregabalin Gabapentin/ Pregabalin Postherpetic neuralgia and focal neuropathy Peripheral neuropathic pain yes TCA (SNRI)‏ yes Tramadol, Oxycodone TCA contraindication no yes TCA contra-indication no no Finnerup et al. Pain 118 (2005) 289–305
    9. 9. 2 nd Line Rx Beyond 2 nd line Rx single RCT, variable multi RCT Dworkin. Arch Neurol 2003:60:1524-34. <ul><li>Antidepressants </li></ul><ul><ul><li>citalopram </li></ul></ul><ul><ul><li>paroxetine </li></ul></ul><ul><ul><li>venlafaxine </li></ul></ul><ul><ul><li>bupropion </li></ul></ul><ul><li>Anticonvulsants </li></ul><ul><ul><li>lamotrigine </li></ul></ul><ul><ul><li>carbamazepine </li></ul></ul><ul><li>mexilitine </li></ul><ul><li>capsaicin </li></ul><ul><li>clonidine </li></ul>
    10. 10. Drug Developments <ul><ul><li>optimal drug strategy </li></ul></ul><ul><ul><li>drug combinations </li></ul></ul><ul><ul><li>drug prophylaxis </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>
    11. 11. Multi-modal Rx <ul><li>Well established for acute pain </li></ul><ul><li>Analgesic league table </li></ul><ul><li>data based on single dose </li></ul><ul><li>post-op dental model </li></ul><ul><li>www.jr2.ox.ac.uk/Bandolier </li></ul>
    12. 12. Combining drugs Neuropathic vs. Nociceptive Drugs <ul><li>------------ </li></ul><ul><li>------------ </li></ul><ul><li>Tramadol </li></ul><ul><li>Opioids </li></ul><ul><li>Tricyclics </li></ul><ul><li>Anticonvulsants </li></ul><ul><li>Capsaicin 0.075% </li></ul><ul><li>Lidoderm </li></ul><ul><li>Paracetamol </li></ul><ul><li>NSAIDs </li></ul><ul><li>Tramadol </li></ul><ul><li>Opioids </li></ul><ul><li>Tricyclics </li></ul><ul><li>------------ </li></ul><ul><li>Capsaicin 0.025% </li></ul><ul><li>------------ </li></ul>
    13. 13. Gabapentin & morphine for acute pain after mastectomy Dirks Anesthesiology 2002; 97: 560-564. <ul><li>DB-RCT, n = 70 </li></ul><ul><li>GBP 1200mg 1h pre-op </li></ul><ul><li>PCA morphine post-op </li></ul><ul><li> morphine, p<0.0001 </li></ul><ul><li>29 (21-33) v 15 mg (10-19) </li></ul><ul><li> VAS rest & cough </li></ul><ul><li>p<0.0001 & 0.018 </li></ul>
    14. 14. Acute Post-op Pain <ul><li>Meta-analysis </li></ul><ul><ul><li>Dahl JB. Acta Anaesth Scand 2004. 48(9):1130-6. </li></ul></ul><ul><ul><li>7 studies – gabapentin + standard analgesic regimen </li></ul></ul><ul><ul><li>Lap chol, VV’s, IH repair etc. </li></ul></ul><ul><ul><li>all show  analgesic requirements at 24 or 48 hr </li></ul></ul><ul><li>Editorial </li></ul><ul><ul><li>Rowbotham D. BJA 2006. 96: 152. </li></ul></ul>
    15. 15. Additive or synergistic? Isobolographs Fletcher D. Anesthesiology 1997;87:317-326. Synergy Diclofenac & Morphine Additive Propacetamol & Morphine
    16. 16. Morphine vs GBP vs Combination for NP Gilron. NEJM 2005; 352: 1324-34. <ul><li>Patients – PHN or DN </li></ul><ul><li>single site over 33 months </li></ul><ul><li>DB-RCT (balanced Latin-square cross over)‏ </li></ul><ul><li>active PBO (lorazepam)‏ </li></ul><ul><li>x 4 crossover for 5 weeks each < 60kg, > 60yr </li></ul><ul><ul><li>Morphine SR 120mg 60 mg </li></ul></ul><ul><ul><li>Gabapentin 3200 mg 2400 mg </li></ul></ul><ul><ul><li>M + G 60, 2400 </li></ul></ul><ul><ul><li>Lorazepam 1.6 mg </li></ul></ul>
    17. 17. Morphine vs GBP vs both for NeuP Gilron. NEJM 2005; 352: 1324-34. <ul><li>Group MG M G PBO </li></ul><ul><li>Pain VAS 3.06 3.7 4.15 4.49 </li></ul><ul><li>p value = 0.04 < 0.001 < 0.001 </li></ul><ul><li>Single dose Combination dose </li></ul><ul><li>M 45 mg (4) 34 mg (3) p <0.05 </li></ul><ul><li>G 2210 mg (90) 1705 mg (83) p <0.05 </li></ul><ul><li>Side effects </li></ul><ul><li>MG > G for constipation p<0.05 </li></ul><ul><li>MG > M for dry mouth p<0.05 </li></ul>
    18. 18. GBP+Oxycontin vs GBP+PBO for NP Hanna M. Poster EFIC 2006. <ul><li>Patients – PDN > 3/12, VAS > 5 </li></ul><ul><li>70 sites across Europe & Australia </li></ul><ul><li>DB-RCT </li></ul><ul><li>x 2 groups for 12 weeks each </li></ul><ul><ul><li>Gabapentin max tolerated dose for 1 month </li></ul></ul><ul><ul><li>Oxycontin 5, 10, 20, 40 mg BD </li></ul></ul><ul><ul><li>PBO BD </li></ul></ul><ul><li>RESULTS </li></ul><ul><li> paracetamol tabs/day </li></ul><ul><li> sleep disturbance </li></ul><ul><li>but = sleep quality </li></ul><ul><li>MPQ & BPI improved & = EQ 5D </li></ul>(33%)‏ ↓ VAS 2.1 vs PBO 1.5
    19. 19. GBP+Oxycontin vs GBP+PBO for NP Hanna M. Poster EFIC 2006. <ul><li>S/E - mostly mild/mod </li></ul><ul><ul><li>88% vs 71% </li></ul></ul><ul><li>SAE </li></ul><ul><ul><li>11% vs 11% </li></ul></ul><ul><li>W/D </li></ul><ul><ul><li>26% vs 22% </li></ul></ul>
    20. 20. Drug Developments <ul><ul><li>optimal drug strategy </li></ul></ul><ul><ul><li>drug combinations </li></ul></ul><ul><ul><li>drug prophylaxis ? </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>
    21. 21. Pre-emptive analgesia?? Patrick Wall
    22. 22. Pre-emptive preoperative analgesia P Wall. Pain 1988; 33:289-90. <ul><li>afferent nociceptive barrage can trigger prolonged spinal cord hyperexcitability </li></ul><ul><li>“ consider the possibility that pre-emptive preoperative analgesia has prolonged effects which long outlast the presence of drugs” </li></ul>
    23. 23. <ul><ul><li>brief incisional phase (1 o )‏ </li></ul></ul>longer inflammatory phase (2 o )‏ Pre-emptive analgesia <ul><li>Reasons for weak </li></ul><ul><li>clinical effect in man </li></ul><ul><li>incomplete analgesia </li></ul><ul><li>inadequate duration </li></ul><ul><li>hyperalgesia not addressed </li></ul>
    24. 24. Incisional (post-op) Pain Brennan TJ. Anesthesiology 2002, 97: 535-537 <ul><li>typically regarded as nociceptive </li></ul><ul><li>tissue injury converts pain system from </li></ul><ul><ul><li>a 'physiological' to a 'pathological' mode </li></ul></ul><ul><li>gabapentin is active in animal models of 'pathological' pain </li></ul>
    25. 25. Gabapentin & morphine for acute pain after mastectomy Dirks Anesthesiology 2002; 97: 560-564. <ul><li>DB-RCT, n = 70 </li></ul><ul><li>GBP 1200mg 1h pre-op </li></ul><ul><li>PCA morphine post-op </li></ul><ul><li> morphine, p<0.0001 </li></ul><ul><li>29 (21-33) v 15 mg (10-19) </li></ul><ul><li> VAS rest & cough </li></ul><ul><li>p<0.0001 & 0.018 </li></ul>
    26. 26. Prophylaxis of PHN Bowsher. J Pain Symp Manage 1997;13:327-31 . <ul><li>DB-RCT, n = 72 (> 60 yrs) acute onset herpes zoster </li></ul><ul><li>amitriptyline 25 mg for 90 days </li></ul><ul><li>PHN prevalence reduced by 50% at 6/12 </li></ul><ul><ul><li>Control 50% </li></ul></ul><ul><ul><li> vs. </li></ul></ul><ul><ul><li>Amitriptyline 25% </li></ul></ul>
    27. 27. ? Prophylaxis of PHN Berry JD. Neurology 2005;65:444-7. <ul><li>DB-RCT x over, n = 26 acute zoster pain </li></ul><ul><li>single dose - gabapentin 900 mg vs. PBO </li></ul><ul><li>Pain VAS improved during 1.5-6 hrs </li></ul><ul><ul><li>66% vs. 33% </li></ul></ul><ul><li>Allodynia area reduced Allodynia intensity reduced </li></ul><ul><ul><li>44% vs. 11% - 54% vs. 38% </li></ul></ul>
    28. 28. Post-op Pain … what outcomes? Wu C. Anesthesiology 2002; 97: 533-534. <ul><li> pain VAS - dynamic </li></ul><ul><li> analgesic dose </li></ul><ul><li> side effects - N/V, HR, RR, M & M </li></ul><ul><li> recovery profile </li></ul><ul><ul><li>PO, PU, PR, mobility, discharge </li></ul></ul><ul><ul><li>hyperalgesia (alteration in CNS processing) -> QST </li></ul></ul><ul><li>HRQoL - “soft” outcome </li></ul><ul><ul><li>global function, patient preferences, cost </li></ul></ul><ul><ul><li>chronic pain </li></ul></ul>
    29. 29. Drug Developments <ul><ul><li>optimal drug strategy </li></ul></ul><ul><ul><li>drug combinations </li></ul></ul><ul><ul><li>drug prophylaxis? </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>
    30. 30. Cannabinoids <ul><li>fat soluble “vitamin M” </li></ul><ul><li>21 carbon alkaloids -60 members </li></ul><ul><li>CB1 R (CNS) </li></ul><ul><li>CB2 R (immune cells) </li></ul><ul><li>delta-9-tetrahydrocannabinol (THC) mimics anandamide </li></ul><ul><ul><li>GW Pharma S/L Sativex spray </li></ul></ul><ul><ul><li>THC:CBD 27:25 mcg/ml </li></ul></ul>
    31. 31. Sativex in NeuP + Allodynia: a 5/52 RCT DB Trial Nurmikko, Serpell et al. Pain (in press)‏ <ul><li>parallel, 63 Sativex & 62 PBO </li></ul><ul><li>remained on usual analgesic Rx </li></ul><ul><li>titrated sprays up to max 24/day </li></ul><ul><li>1 ° outcome – VAS pain </li></ul><ul><li>2 ° outcomes </li></ul><ul><ul><li>- NPS, sleep, PDI, PGIC </li></ul></ul><ul><ul><li>allodynia – punctate & dynamic </li></ul></ul>
    32. 32. 7.5 7.0 6.5 6.0 5.5 5.0 4.5 0 Baseline Wk 2 Wk 3 Wk4 Wk 5 Pain Baseline Titration Wk 1 Wk 2 Wk 3 Wk 4 Sleep disturbance * P<0.05 4 3 2 1 0 ## P<0.001 CBM Placebo Wk 1 ** # P<0.01 ## ## ## ## # ** P<0.01 ** ** * Sativex in NeuP + Allodynia: a 5/52 RCT DB Trial Nurmikko, Serpell et al. Pain (in press)‏ -0.52 -1.48 <ul><li>All 2° outcomes +ve </li></ul><ul><li>- NPS, sleep, PDI, PGIC </li></ul><ul><li>allodynia: punctate & dynamic </li></ul><ul><li>W/D due to S/E 18% vs. 3% </li></ul>
    33. 33. Short term adverse effects <ul><li>Usually transient & resolve during titration </li></ul><ul><li>Depression of CNS </li></ul><ul><ul><li>Dizziness </li></ul></ul><ul><ul><li>Dry mouth </li></ul></ul><ul><ul><li>Sedation </li></ul></ul><ul><ul><li>myalgia or muscle weakness </li></ul></ul><ul><ul><li>palpitations </li></ul></ul><ul><ul><li>mood changes </li></ul></ul>
    34. 34. Canada & Cannabis
    35. 35. Canada & Cannabis www.torontohemp.com
    36. 36. Lidocaine Plaster: A new treatment option <ul><li>• Soft, stretchy, adhesive plaster </li></ul><ul><li>• Hydrogel-plaster </li></ul><ul><li>• 14 x 10 cm </li></ul><ul><li>• 5% lidocaine (total 700 mg)‏ </li></ul><ul><li>• applied 12 hrs ON, 12 hrs OFF </li></ul><ul><li>Indication: </li></ul><ul><li>• Topical treatment of PHN </li></ul>
    37. 37. Post-op Pain & Molecules <ul><li>Drug developments </li></ul><ul><ul><li>algorithm </li></ul></ul><ul><ul><li>combinations </li></ul></ul><ul><ul><li>prevention? </li></ul></ul><ul><ul><li>new drugs </li></ul></ul>[email_address]
    38. 38. The Patient

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