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