Chronic Pain After Surgery Molecules

Mick Serpell Senior Lecturer Post-op Pain & Molecules
Drug developments
algorithm
combinations
prevention?
new drugs

Combination Pain
post-operative
PHN, PDN trauma O/A, Rh/A
neuropathic  ---------------------------  nociceptive
(mixed)‏

Drug Developments
optimal drug strategy
drug combinations
drug prophylaxis
new drugs

WHO ladder - Nociceptive Pain
Step 1
Paracetamol
NSAIDs or COX II?
Step 2
codeine, dihydrocodeine, dextropropoxyphene, meptazinol
often as co-analgesics ie: co-codamol
Step 2  3 Tramadol
Step 3
morphine, diamorphine, pethidine
methadone, fentanyl, buprenorphine
oxycodone, hydromorphone

Neuropathic analgesics
Adjuvants
tricyclic antidepressants
anticonvulsants
others
opioids
sodium channel blockers
NMDA antagonists
capsaicin
cannabis

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%

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

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

2 nd Line Rx Beyond 2 nd line Rx single RCT, variable multi RCT Dworkin. Arch Neurol 2003:60:1524-34.
Antidepressants
citalopram
paroxetine
venlafaxine
bupropion
Anticonvulsants
lamotrigine
carbamazepine
mexilitine
capsaicin
clonidine

Drug Developments
drug combinations
drug prophylaxis
new drugs

Multi-modal Rx
Well established for acute pain
Analgesic league table
data based on single dose
post-op dental model
www.jr2.ox.ac.uk/Bandolier

Combining drugs Neuropathic vs. Nociceptive Drugs
------------
------------
Tramadol
Opioids
Tricyclics
Anticonvulsants
Capsaicin 0.075%
Lidoderm
Paracetamol
NSAIDs
Tramadol
Opioids
Tricyclics
------------
Capsaicin 0.025%
------------

Gabapentin & morphine for acute pain after mastectomy Dirks Anesthesiology 2002; 97: 560-564.
DB-RCT, n = 70
GBP 1200mg 1h pre-op
PCA morphine post-op
 morphine, p<0.0001
29 (21-33) v 15 mg (10-19)
 VAS rest & cough
p<0.0001 & 0.018

Acute Post-op Pain
Meta-analysis
Dahl JB. Acta Anaesth Scand 2004. 48(9):1130-6.
7 studies – gabapentin + standard analgesic regimen
Lap chol, VV’s, IH repair etc.
all show  analgesic requirements at 24 or 48 hr
Editorial
Rowbotham D. BJA 2006. 96: 152.

Additive or synergistic? Isobolographs Fletcher D. Anesthesiology 1997;87:317-326. Synergy Diclofenac & Morphine Additive Propacetamol & Morphine

Morphine vs GBP vs Combination for NP Gilron. NEJM 2005; 352: 1324-34.
Patients – PHN or DN
single site over 33 months
DB-RCT (balanced Latin-square cross over)‏
active PBO (lorazepam)‏
x 4 crossover for 5 weeks each < 60kg, > 60yr
Morphine SR 120mg 60 mg
Gabapentin 3200 mg 2400 mg
M + G 60, 2400
Lorazepam 1.6 mg

Morphine vs GBP vs both for NeuP Gilron. NEJM 2005; 352: 1324-34.
Group MG M G PBO
Pain VAS 3.06 3.7 4.15 4.49
p value = 0.04 < 0.001 < 0.001
Single dose Combination dose
M 45 mg (4) 34 mg (3) p <0.05
G 2210 mg (90) 1705 mg (83) p <0.05
Side effects
MG > G for constipation p<0.05
MG > M for dry mouth p<0.05

GBP+Oxycontin vs GBP+PBO for NP Hanna M. Poster EFIC 2006.
Patients – PDN > 3/12, VAS > 5
70 sites across Europe & Australia
DB-RCT
x 2 groups for 12 weeks each
Gabapentin max tolerated dose for 1 month
Oxycontin 5, 10, 20, 40 mg BD
PBO BD
RESULTS
 paracetamol tabs/day
 sleep disturbance
but = sleep quality
MPQ & BPI improved & = EQ 5D
(33%)‏ ↓ VAS 2.1 vs PBO 1.5

GBP+Oxycontin vs GBP+PBO for NP Hanna M. Poster EFIC 2006.
S/E - mostly mild/mod
88% vs 71%
SAE
11% vs 11%
W/D
26% vs 22%

Drug Developments
drug combinations
drug prophylaxis ?
new drugs

Pre-emptive analgesia?? Patrick Wall

Pre-emptive preoperative analgesia P Wall. Pain 1988; 33:289-90.
afferent nociceptive barrage can trigger prolonged spinal cord hyperexcitability
“ consider the possibility that pre-emptive preoperative analgesia has prolonged effects which long outlast the presence of drugs”

brief incisional phase (1 o )‏
longer inflammatory phase (2 o )‏ Pre-emptive analgesia
Reasons for weak
clinical effect in man
incomplete analgesia
inadequate duration
hyperalgesia not addressed

Incisional (post-op) Pain Brennan TJ. Anesthesiology 2002, 97: 535-537
typically regarded as nociceptive
tissue injury converts pain system from
a 'physiological' to a 'pathological' mode
gabapentin is active in animal models of 'pathological' pain

Gabapentin & morphine for acute pain after mastectomy Dirks Anesthesiology 2002; 97: 560-564.
DB-RCT, n = 70
GBP 1200mg 1h pre-op
PCA morphine post-op
 morphine, p<0.0001
29 (21-33) v 15 mg (10-19)
 VAS rest & cough
p<0.0001 & 0.018

Prophylaxis of PHN Bowsher. J Pain Symp Manage 1997;13:327-31 .
DB-RCT, n = 72 (> 60 yrs) acute onset herpes zoster
amitriptyline 25 mg for 90 days
PHN prevalence reduced by 50% at 6/12
Control 50%
vs.
Amitriptyline 25%

? Prophylaxis of PHN Berry JD. Neurology 2005;65:444-7.
DB-RCT x over, n = 26 acute zoster pain
single dose - gabapentin 900 mg vs. PBO
Pain VAS improved during 1.5-6 hrs
66% vs. 33%
Allodynia area reduced Allodynia intensity reduced
44% vs. 11% - 54% vs. 38%

Post-op Pain … what outcomes? Wu C. Anesthesiology 2002; 97: 533-534.
 pain VAS - dynamic
 analgesic dose
 side effects - N/V, HR, RR, M & M
 recovery profile
PO, PU, PR, mobility, discharge
hyperalgesia (alteration in CNS processing) -> QST
HRQoL - “soft” outcome
global function, patient preferences, cost
chronic pain

Drug Developments
drug combinations
drug prophylaxis?
new drugs

Cannabinoids
fat soluble “vitamin M”
21 carbon alkaloids -60 members
CB1 R (CNS)
CB2 R (immune cells)
delta-9-tetrahydrocannabinol (THC) mimics anandamide
GW Pharma S/L Sativex spray
THC:CBD 27:25 mcg/ml

Sativex in NeuP + Allodynia: a 5/52 RCT DB Trial Nurmikko, Serpell et al. Pain (in press)‏
parallel, 63 Sativex & 62 PBO
remained on usual analgesic Rx
titrated sprays up to max 24/day
1 ° outcome – VAS pain
2 ° outcomes
- NPS, sleep, PDI, PGIC
allodynia – punctate & dynamic

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
All 2° outcomes +ve
- NPS, sleep, PDI, PGIC
allodynia: punctate & dynamic
W/D due to S/E 18% vs. 3%

Short term adverse effects
Usually transient & resolve during titration
Depression of CNS
Dizziness
Dry mouth
Sedation
myalgia or muscle weakness
palpitations
mood changes

Canada & Cannabis

Canada & Cannabis www.torontohemp.com

Lidocaine Plaster: A new treatment option
• Soft, stretchy, adhesive plaster
• Hydrogel-plaster
• 14 x 10 cm
• 5% lidocaine (total 700 mg)‏
• applied 12 hrs ON, 12 hrs OFF
Indication:
• Topical treatment of PHN

Post-op Pain & Molecules
Drug developments
algorithm
combinations
prevention?
new drugs
[email_address]

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Chronic Pain After Surgery Molecules

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