Mick Serpell Mick Serpell Senior LecturerSenior Lecturer

Post-op Pain Post-op Pain& Molecules& Molecules

Drug developmentsDrug developments– algorithmalgorithm– combinationscombinations– prevention? prevention? – new drugsnew drugs

Combination PainCombination Pain

post-operativepost-operativePHN, PDNPHN, PDN trauma trauma O/A, Rh/A O/A, Rh/Aneuropathic neuropathic ------------------------------------------------------ nociceptive nociceptive

(mixed)(mixed)

Drug DevelopmentsDrug Developments

– optimal drug strategyoptimal drug strategy– drug combinationsdrug combinations– drug prophylaxisdrug prophylaxis– new drugsnew drugs

WHO ladder - Nociceptive PainWHO ladder - Nociceptive Pain Step 1Step 1

– ParacetamolParacetamol– NSAIDs or COX II?NSAIDs or COX II?

Step 2Step 2 – codeine, dihydrocodeine, dextropropoxyphene, meptazinol codeine, dihydrocodeine, dextropropoxyphene, meptazinol – often as co-analgesics ie: co-codamol often as co-analgesics ie: co-codamol

Step 2 Step 2 3 3 TramadolTramadol

Step 3Step 3 – morphine, diamorphine, morphine, diamorphine, pethidinepethidine– methadone, fentanyl, buprenorphinemethadone, fentanyl, buprenorphine– oxycodone, hydromorphoneoxycodone, hydromorphone

Neuropathic analgesicsNeuropathic analgesics

AdjuvantsAdjuvants– tricyclic antidepressantstricyclic antidepressants– anticonvulsantsanticonvulsants

othersothers– opioidsopioids– sodium channel blockerssodium channel blockers– NMDA antagonistsNMDA antagonists– capsaicincapsaicin– cannabiscannabis

NNT0 2 4 6 8 10 12

Topiramate*Antidepressants, SSRI

Capsaicin

NMDA antagonists*Mexiletine*

Antidepressants, SNRI

Gabapentin/pregabalinTramadol

Opioids

Carbamazepine/lamotrigine/phenytoin

ValproateTricyclic 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)

NNH0 5 10 15 20

Antidepressants, SSRI

ValproateMexiletine

Carbamazepine/lamotrigine/phenytoin

Gabapentin/pregabalinOpioids

Antidepressants, SNRITricyclic antidepressants

NMDA antagonistsCapsaicinTramadol

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

noyes TCA contra-indication

no

no

Finnerup et al. Pain 118 (2005) 289–305

22ndnd Line Rx Line Rx Beyond 2Beyond 2ndnd line Rx line Rxsingle RCT, variable multi RCT single RCT, variable multi RCT Dworkin. Arch Neurol 2003:60:1524-34.Dworkin. Arch Neurol 2003:60:1524-34.

AntidepressantsAntidepressants– citalopramcitalopram– paroxetineparoxetine– venlafaxinevenlafaxine– bupropionbupropion

AnticonvulsantsAnticonvulsants– lamotriginelamotrigine– carbamazepinecarbamazepine

mexilitinemexilitine capsaicincapsaicin clonidineclonidine

Drug DevelopmentsDrug Developments

– optimal drug strategyoptimal drug strategy– drug combinationsdrug combinations– drug prophylaxisdrug prophylaxis– new drugsnew drugs

Multi-modal RxMulti-modal Rx

Well establishedWell established for acute pain for acute pain

Analgesic league tableAnalgesic league tabledata based on data based on single dosesingle dosepost-op post-op dentaldental model model

www.jr2.ox.ac.uk/Bandolierwww.jr2.ox.ac.uk/Bandolier

Combining drugsCombining drugsNeuropathic vs. Neuropathic vs. NociceptiveNociceptive DrugsDrugs

------------------------ ------------------------ TramadolTramadol OpioidsOpioids TricyclicsTricyclics AnticonvulsantsAnticonvulsants Capsaicin 0.075%Capsaicin 0.075% LidodermLidoderm

ParacetamolParacetamol NSAIDsNSAIDs TramadolTramadol OpioidsOpioids TricyclicsTricyclics ------------------------ Capsaicin 0.025%Capsaicin 0.025% ------------------------

Gabapentin & morphine for Gabapentin & morphine for acute pain after mastectomyacute pain after mastectomy

Dirks Anesthesiology 2002; 97: 560-Dirks Anesthesiology 2002; 97: 560-564.564.

DB-RCT, n = 70DB-RCT, n = 70 GBPGBP 1200mg 1h pre-op 1200mg 1h pre-op PCA PCA morphinemorphine post-op post-op

morphine, p<0.0001morphine, p<0.0001 29 (21-33) v 15 mg (10-19) 29 (21-33) v 15 mg (10-19) VAS rest & VAS rest & coughcough p<0.0001 & 0.018p<0.0001 & 0.018

Acute Post-op PainAcute Post-op Pain

Meta-analysis Meta-analysis – Dahl JB. Acta Anaesth Scand 2004. 48(9):1130-6. Dahl JB. Acta Anaesth Scand 2004. 48(9):1130-6. – 7 studies – gabapentin + standard analgesic regimen7 studies – gabapentin + standard analgesic regimen– Lap chol, VV’s, IH repair etc.Lap chol, VV’s, IH repair etc.– all show all show analgesic requirements at 24 or 48 hr analgesic requirements at 24 or 48 hr

EditorialEditorial– Rowbotham D. BJA 2006. 96: 152.Rowbotham D. BJA 2006. 96: 152.

Additive or synergistic?Additive or synergistic?IsobolographsIsobolographs

Fletcher D. Anesthesiology 1997;87:317-Fletcher D. Anesthesiology 1997;87:317-326.326.

SynergySynergyDiclofenac & MorphineDiclofenac & Morphine

AdditiveAdditive Propacetamol & MorphinePropacetamol & Morphine

Morphine vs GBP vs Morphine vs GBP vs CombinationCombination for NP for NP Gilron. NEJM 2005; 352: 1324-34.Gilron. NEJM 2005; 352: 1324-34.

Patients – PHN or DNPatients – PHN or DN single sitesingle site over 33 months over 33 months DB-RCT (balanced Latin-square cross over)DB-RCT (balanced Latin-square cross over) activeactive PBO (lorazepam) PBO (lorazepam) x 4 crossover for 5 weeks eachx 4 crossover for 5 weeks each < 60kg, > 60yr< 60kg, > 60yr

– Morphine SRMorphine SR 120mg120mg 60 mg60 mg– GabapentinGabapentin 3200 mg3200 mg 2400 mg2400 mg– M + GM + G 60, 240060, 2400– LorazepamLorazepam 1.6 mg1.6 mg

Morphine vs GBP vs both for NeuPMorphine vs GBP vs both for NeuP Gilron. NEJM 2005; 352: 1324-34.Gilron. NEJM 2005; 352: 1324-34.

GroupGroupMGMG M M GG PBOPBO Pain VAS Pain VAS 3.063.06 3.7 3.7 4.154.15 4.494.49 p value p value = 0.04 = 0.04 < 0.001< 0.001 < 0.001< 0.001

Single doseSingle dose Combination doseCombination dose M M 45 mg (4)45 mg (4) 34 mg (3)34 mg (3) p <0.05p <0.05 G 2210 mg (90)G 2210 mg (90) 1705 mg (83) 1705 mg (83) p <0.05p <0.05

Side effectsSide effects MG > G for constipation MG > G for constipation p<0.05p<0.05 MG > M for dry mouthMG > M for dry mouth p<0.05p<0.05

GBP+Oxycontin vs GBP+PBO GBP+Oxycontin vs GBP+PBO for NP for NP Hanna M. Poster EFIC 2006.Hanna M. Poster EFIC 2006.

Patients – PDN > 3/12, VAS > 5Patients – PDN > 3/12, VAS > 5 70 sites across Europe & Australia70 sites across Europe & Australia DB-RCT DB-RCT x 2 groups for 12 weeks eachx 2 groups for 12 weeks each

– GabapentinGabapentin max tolerated dose for 1 monthmax tolerated dose for 1 month– OxycontinOxycontin 5, 10, 20, 40 mg BD5, 10, 20, 40 mg BD – PBOPBO BDBD

RESULTSRESULTS paracetamol tabs/dayparacetamol tabs/day

sleep disturbance sleep disturbance but = sleep qualitybut = sleep quality

MPQ & BPI improved MPQ & BPI improved & = & = EQ 5DEQ 5D

(33%)(33%)↓ ↓ VAS 2.1 vs PBO 1.5VAS 2.1 vs PBO 1.5

GBP+Oxycontin vs GBP+PBO for NPGBP+Oxycontin vs GBP+PBO for NP Hanna M. Poster EFIC 2006.Hanna M. Poster EFIC 2006.

S/E - mostly mild/modS/E - mostly mild/mod– 88%88% vsvs 71%71%

SAESAE– 11%11% vsvs 11%11%

W/DW/D– 26%26% vsvs 22%22%

Drug DevelopmentsDrug Developments

– optimal drug strategyoptimal drug strategy– drug combinationsdrug combinations– drug prophylaxis ?drug prophylaxis ?– new drugsnew drugs

Pre-emptive analgesia?? Pre-emptive analgesia??

Patrick Wall Patrick Wall

Pre-emptive preoperative analgesiaPre-emptive preoperative analgesiaP Wall. Pain 1988; 33:289-90.P Wall. Pain 1988; 33:289-90.

afferent nociceptive barrage afferent nociceptive barrage can trigger prolonged spinal can trigger prolonged spinal cord hyperexcitabilitycord hyperexcitability

““consider the possibility that consider the possibility that pre-emptive preoperative pre-emptive preoperative analgesia has prolonged analgesia has prolonged effects which long outlast effects which long outlast the presence of drugs”the presence of drugs”

brief incisional phase (1brief incisional phase (1oo))

longer longer inflammatory inflammatory phase (2phase (2oo))

Pre-emptive analgesiaPre-emptive analgesia

Reasons for weak Reasons for weak clinical effect in manclinical effect in man incomplete analgesiaincomplete analgesia inadequate durationinadequate duration hyperalgesia not addressedhyperalgesia not addressed

Incisional (post-op) PainIncisional (post-op) Pain Brennan TJ. Anesthesiology 2002, 97: 535- Brennan TJ. Anesthesiology 2002, 97: 535-

537537

typically regarded as typically regarded as nociceptivenociceptive tissue injury converts pain system from tissue injury converts pain system from

– a 'physiological' to a 'pathological' mode a 'physiological' to a 'pathological' mode gabapentin is active in animal models of 'pathological' paingabapentin is active in animal models of 'pathological' pain

Gabapentin & morphine for Gabapentin & morphine for acute pain after mastectomyacute pain after mastectomy

Dirks Anesthesiology 2002; 97: 560-Dirks Anesthesiology 2002; 97: 560-564.564.

DB-RCT, n = 70DB-RCT, n = 70 GBPGBP 1200mg 1h pre-op 1200mg 1h pre-op PCA PCA morphinemorphine post-op post-op

morphine, p<0.0001morphine, p<0.0001 29 (21-33) v 15 mg (10-19) 29 (21-33) v 15 mg (10-19) VAS rest & VAS rest & coughcough p<0.0001 & 0.018p<0.0001 & 0.018

Prophylaxis of PHNProphylaxis of PHNBowsher. J Pain Symp Manage 1997;13:327-31Bowsher. J Pain Symp Manage 1997;13:327-31..

DB-RCT, n = 72 (> 60 yrs) acute onset herpes zosterDB-RCT, n = 72 (> 60 yrs) acute onset herpes zoster

amitriptylineamitriptyline 25 mg for 90 days 25 mg for 90 days

PHN prevalence reduced by 50% at 6/12PHN prevalence reduced by 50% at 6/12– Control Control 50% 50%

vs.vs.– Amitriptyline Amitriptyline 25%25%

? Prophylaxis of PHN? Prophylaxis of PHNBerry JD. Neurology 2005;65:444-7.Berry JD. Neurology 2005;65:444-7.

DB-RCT x over, n = 26 DB-RCT x over, n = 26 acute zoster painacute zoster pain

single dosesingle dose - - gabapentingabapentin 900 mg vs. PBO 900 mg vs. PBO

Pain VAS improved during 1.5-6 hrsPain VAS improved during 1.5-6 hrs– 66% vs. 33%66% vs. 33%

Allodynia area reducedAllodynia area reduced Allodynia intensity Allodynia intensity reducedreduced– 44% vs. 11%44% vs. 11% - 54% vs. 38%- 54% vs. 38%

Post-op Pain … what outcomes?Post-op Pain … what outcomes? Wu C. Anesthesiology 2002; 97: 533-Wu C. Anesthesiology 2002; 97: 533-

534.534.

pain VAS - pain VAS - dynamicdynamic analgesic doseanalgesic dose side effects - N/V, HR, RR, M & Mside effects - N/V, HR, RR, M & M recovery profilerecovery profile

– PO, PU, PR, mobility, discharge PO, PU, PR, mobility, discharge – hyperalgesia (alteration in CNS processing) hyperalgesia (alteration in CNS processing) → → QSTQST

HRQoL - “soft” outcomeHRQoL - “soft” outcome– global function, patient preferences, cost global function, patient preferences, cost – chronic painchronic pain

Drug DevelopmentsDrug Developments

– optimal drug strategyoptimal drug strategy– drug combinationsdrug combinations– drug prophylaxis?drug prophylaxis?– new drugsnew drugs

CannabinoidsCannabinoids fat soluble fat soluble “vitamin M”“vitamin M”

21 carbon alkaloids -60 members21 carbon alkaloids -60 members

CB1 R (CNS) CB1 R (CNS) CB2 R (immune cells) CB2 R (immune cells)

delta-9-tetrahydrocannabinol delta-9-tetrahydrocannabinol (THC) mimics anandamide(THC) mimics anandamide– GW Pharma S/L Sativex sprayGW Pharma S/L Sativex spray– THC:CBD 27:25 mcg/mlTHC:CBD 27:25 mcg/ml

Sativex in NeuP + Allodynia: Sativex in NeuP + Allodynia: a 5/52 RCT DB Triala 5/52 RCT DB Trial Nurmikko, Serpell et al. Pain (in press)Nurmikko, Serpell et al. Pain (in press)

parallel, 63 Sativex & 62 PBOparallel, 63 Sativex & 62 PBO remained on usual analgesic Rxremained on usual analgesic Rx titrated sprays up to max 24/daytitrated sprays up to max 24/day 11°° outcome – VAS pain outcome – VAS pain 22°° outcomes outcomes

- NPS, sleep, PDI, PGIC- NPS, sleep, PDI, PGIC- allodynia – punctate & dynamicallodynia – punctate & dynamic

7.5

7.06.5

6.0

5.55.0

4.5 0

Baseline Wk 2 Wk 3 Wk4 Wk 5

PainPain

Baseline Titration Wk 1 Wk 2 Wk 3

Wk 4

Sleep disturbanceSleep disturbance

* P<0.05

4

3

2

1

0##P<0.001

CBM

Placebo

Wk 1

**

#P<0.01######## #

** P<0.01

** **

*

No. of Sprays (by visit) in Long-term Extension Phase

0

2

4

6

8

10

12

14

16

0 10 20 30 40 50 60 70

Study Week

Mea

n (+

/- SE

) dai

ly n

o. o

f Spr

ays

. n = 82 62 46 44 33 28 24 20 15

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 Short term adverse effectseffects Usually transient & resolve during Usually transient & resolve during

titrationtitration Depression of CNSDepression of CNS

– DizzinessDizziness– Dry mouth Dry mouth – SedationSedation

– myalgia or muscle weaknessmyalgia or muscle weakness– palpitationspalpitations– mood changesmood changes

Canada & CannabisCanada & Cannabis

Canada & CannabisCanada & Cannabis

www.torontohemp.comwww.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 PainPost-op Pain& Molecules& Molecules

Drug developmentsDrug developments– algorithmalgorithm– combinationscombinations– prevention? prevention? – new drugsnew drugs

mgserpell@cheerful.commgserpell@cheerful.com

The PatientThe Patient