A/Professor Arun AggarwalRoyal Prince Alfred HospitalPain Management CentreSYDNEY AUSTRALIA

International Conference on Pain Medicine 2015 – Chicago

NEUROPATHIC PAIN NEUROPATHIC PAIN MEDICATION UPDATE: MEDICATION UPDATE:

20152015

Professor Aggarwal is on medical advisory boards, received sponsorship or honoraria from the following companies:

BioCSLHospiraiNovaMundipharmaPfizerUCB

DISCLOSURES

NEUROPATHIC PAIN – ISSUES AND CHALLENGES

Prevalence 25-50% patients treated at Pain clinics

Complex pathophysiology Precise mechanisms unknown Multiple mechanisms involved

Under-assessed and under-treated

Available treatments provide only modest reduction of pain

THE BIOPSYCHOSOCIAL PAIN MODEL

Gatchel RJ, Peng YB, Peters ML, et al.. Psychol Bull. 2007;133:581-624.

THE MULTIMODAL APPROACH TO PAIN MANAGEMENT

1. Pergolizzi J. Curr Med Res Opin 2013;29(9):1127-1135.

THE MAJORITY OF PATIENTS ( 1084) IN 2007 PRESCRIBED DRUGS WITH NO DEMONSTRATED EFFICACY IN

NEUROPATHIC PAIN

Pati

ents

pre

scri

bed

trea

tmen

ts

for

neur

opat

hic

pain

(%

)

Graph adapted from a Belgian observational study of neuropathic pain treatment in daily practice 1084 patientsGraph adapted from a Belgian observational study of neuropathic pain treatment in daily practice 1084 patients

**

**

**

AEDS, some antidepressants, and opioids have demonstrated efficacy in neuropathic pain

AEDS, some antidepressants, and opioids have demonstrated efficacy in neuropathic pain

**

****

**

Generally involves use of anti-convulsants and / or anti-depressant medication

Even with the current generation of drugs, effective analgesia is achieved in <50% of cases

Despite advances in research and clinical trials, NNT for most drugs is between 3-5

PHARMACOTHERAPYPHARMACOTHERAPY

Carbamazepine 2.3 (CI 1.6 - 3.8)Amitriptyline 2.4 (CI 2.4 – 4.0)

Dextromethophan2.5 (CI 1.6 - 5.4)Gabapentin 3.8 (CI 3.5 - 5.7) Tramadol 3.9 (CI 2.7 - 6.3)Lamotrigine 4.0 (CI 2.1 - 4.2)

Pregabalin 4.2 (CI 3.9 – 6.6)Topiramate 7.4 (CI 4.3 – 28.5)

NNT’S FOR DIABETIC PERIPHERAL NNT’S FOR DIABETIC PERIPHERAL NEUROPATHYNEUROPATHY

NNH - major harm not statistically significant for any drug compared to placebo

Carbamazepine 3.7 (CI 2.4 - 7.8)Amitriptyline 3.7 (CI 2.9 - 5.2)Gabapentin 3.5 (CI 2.0 - 3.2)

Opioids 4.2 (CI 3.2 - 5.6)Topiramate 6.3 (CI 5.1 - 8.1)Pregabalin 6.5 (CI 4.0 – 8.3)

NNH’S FOR DIABETIC NNH’S FOR DIABETIC PERIPHERAL NEUROPATHYPERIPHERAL NEUROPATHY

Tolerable dose vs therapeutic dose Serum level vs empiric recommendations

Start low Increase slow

Combinations may improve tolerable dose

Continue at maximum tolerable dose

Continue for maximum duration of time to see maximum benefit

DOSAGE AND DURATIONDOSAGE AND DURATION

WHO ANALGESIC LADDER WHO ANALGESIC LADDER AUSTRALIA 2015 (NOCICEPTIVE)AUSTRALIA 2015 (NOCICEPTIVE)

Non-opioids (paracetamol, NSAID’s, COX-2)

Persistent pain or increasing pain

Weak opioids (codeine, tramadol*, buprenorphine)for mild-moderate pain

+/- non opioids +/- adjuvants (TCA#, AED^)

Persistent pain or increasing pain

Strong opioids (oxycodone, tapendatol, Targin, morphine, fentanyl)

for moderate-severe pain+/- non opioids +/- adjuvants

SymptomsSevere

Mild

Su

perv

ise

d

* TGA indicated for moderate to severe pain; ^pregabalin is TGA indicated for neuropathic pain; #not TGA-indicated for pain management

Anti-Convulsants Carbamazepine, Oxcarbazepine Valproate, PhenytoinGabapentin, Pregabalin, Lamotrigine, Topiramate, Levetiracetam, TiagabineLacosamide (Vimpat), ZonisamideClonazepam

Anti-DepressantsAmitriptyline, Nortriptyline, ImipramineDuloxetine

OpioidsTramadol, Buprenorphine, Oxycodone (Targin), Tapendatol, Morphine, Fentanyl

Miscellanous Baclofen, Mexilitene, Clonidine, Capsaicin cream

N-methyl-D-aspartate (NMDA) blockers Dextromethorphan, Ketamine, Memantine

Botulinum Toxin

Vitamin B12

Versatis – Lignocaine 5% dermal patch

NEUROPATHIC PAIN THERAPIES NEUROPATHIC PAIN THERAPIES AUSTALIA 2015 AUSTALIA 2015 (AGGARWAL)(AGGARWAL)

15

RATIONAL POLYTHERAPY

Calendar year

1840 1860 1880 1900 1920 1940 1960 1980 20000

5

10

15

20

BromidePhenobarbital

Phenytoin Primidone

Ethosuximide

Sodium Valproate

Benzodiazepines

Carbamazepine

Antiepileptic drugs

VigabatrinZonisamide

Lamotrigine

FelbamateGabapentin

TopiramateFosphenytoin

OxcarbazepineTiagabine

Levetiracetam

Pregabalin

Stiripentol

RufinamideLacosamide

Eslicarbazepine

Retigabine

APS-preferred medications available in Australia for treatment of neuropathic pain conditions*

Noradrenergic antidepressants

Nortriptylinea, amitriptylinea, venlafaxinea, duloxetinea

Calcium channel alpha 2-delta ligands

Gabapentin, pregabalin

Sodium channel blockers Topical lignocainea

Opioid agonist Morphine, oxycodone, methadonePartial opioid agonist /monaminergic

Tramadol

AUSTRALIAN PAIN SOCIETY (APS) 2008 RECOMMENDATIONS

FOR THE PHARMACOLOGIC MANAGEMENT OF NP

NP, neuropathic painNP, neuropathic pain

a * Non-prioritisedNortriptyline, amitriptyline, venlafaxine, topical lignocaine are not indicated for the treatment of neuropathic pain in Australia; duloxetine is indicated for the treatment of diabetic peripheral neuropathic pain in Australia

a * Non-prioritisedNortriptyline, amitriptyline, venlafaxine, topical lignocaine are not indicated for the treatment of neuropathic pain in Australia; duloxetine is indicated for the treatment of diabetic peripheral neuropathic pain in Australia

The APS recognises that multiple drug regimens may increase the successful outcome rate, that the drugs may require rotation, and that effectiveness and side-effects

must be continually monitored

SODIUM VALPROATESODIUM VALPROATE

Better tolerated than Carbamazepine

Only 1 small clinical trial in pain 89 patients – NNT 2.3

Increases activity of the inhibitory transmitter GABAt ½ 8-12 hrs

200mg nocte increasing to 400mg bd

SE: GIT, weight gain, tremorHepatic dysfunctionMonitor LFT’s

57 yoLeft TN affecting upper jaw since 2006Sharp, stabbing Increased by chewing, eating and brushing teethSince May 2009, constant burning sensation lower jaw

Dental proceduresNo improvement

Carbamazepine Improved pain, but cognitive side effects

PregabalinHeadaches

MRS LT

Epilim commenced 200 mg nocte Pain improved 6-7/10 to 4/10

Increased to 200 mg bd after 2 weeks Pain free Constant burning sensation was present for over 6

months

No side effects Life back and feels marvellous Remained pain free for next 5 years (2014)

MRS LT

Pain relieving (anti-allodynic) activity of a CNS-active amide derivative of a chiral isomer of valproic acid Diastereomers (2R,3S)-VCD and (2S,3S)-VCD Rats using spinal nerve ligation model of neuropathic

pain

Both showed a dose-related reversal of tactile allodynia (2S,3S)-VCD was more potent and has a potential to become a candidate for development as a new drug for treating neuropathic pain

STEREOISOMERS OF VALNOCTAMIDE (VCD) KAUFMANN 2010

OXCARBAMAZEPINE (TRILEPTAL)OXCARBAMAZEPINE (TRILEPTAL)

Carbamazepine without the side effects Less Na, dizziness, drowsiness and lethergy

Slightly less potent Higher doses needed

4 studies in Canada and Europe As effective as Carbamazepine (70-80% response)

Not covered by PBS Approx $90 per month

MRS RFMRS RF

88 yo

TN diagnosed 30 years ago (age 68) Symptoms responded well to Carbamazepine

Recurrence of pain 20 years later

GP commenced Gabapentin up to 300mg tds Ongoing constant burning pain Intermittent sharp electric shock pain when chews/talks Increased sensitivity to touch

Ozcarbamazepine 75 mg daily increasing to 150 mg bd Pain free and able to chew and talk

Weaned off Gabapentin

LACOSAMIDE (VIMPAT)

Selectively enhances slow inactivation of voltage-gated sodium channels Reduced hyper-excitabilitity of membranes

Interacts with collapsin response mediator protein-2 (CRMP-2) which blocks N-type voltage-gated calcium channel (Cav 2.2) Phosphoprotein expressed in nervous system Involved in neuronal differentiation and control of axonal outgrowth

Oral bioavailability 100%Renal excretion

Starting at 50 mg bd increasing to 200 mg bd

MR AM

82 yo man 20 years of constant burning sensation soles of both feet Frequent sharp shooting pain NCS – no evidence of large fibre peripheral neuropathy

Tried Carbamazepine (allergy), Sodium Vaproate, Amitriptyline, Phenytoin and Clonazepam

Progress Gabapentin – improved pain Amitriptyline added to Gabapentin

Pain free for 1st time in 5 years with recurrence over next 6 months Weaned off Gabapentin and commenced Lyrica

Improved pain but side effects on higher dose Duloxetine added and Pregabalin reduced

Pain increased as Lyrica reduced Levetiracetam, then Oxcarbamazepine tried – No improvement

Lacosamide (Vimpat) - 50 mg bd improved pain 2/10 No sharp stabbing pain Increased to 100mg bd - pain manageable at 1/10

ZONISAMIDE

Blocks Na+ channels (similar to Carbamazepine) Reduces T-type Ca + + currents Enhances GABA release Modulates glutamate-mediated synaptic transmission

TAPENTADOL (PALEXIATAPENTADOL (PALEXIA®®) SR: ) SR: MECHANISM OF ACTIONMECHANISM OF ACTION††

(COMPLEMENTARY AND INTERACT SYNERGISTICALLY)(COMPLEMENTARY AND INTERACT SYNERGISTICALLY)

Refs: 1. Pergolizzi et al. Pain Prac 2011; 12(4):290–306. 2. Argoff C. Curr Med Res Opin 2011; 27(10):2019–31. 3. Kress HG. Eur J Pain 2010; 14(8):781–3. 4. eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; Mar 2013 Accessed: 5 May 2014. 5. Ballantyne JC & Shin NS et al. Clin J Pain 2008; 24(6):469–78. 6. McNicol ED et al. Cochrane Database Syst Rev 2013; (Issue 8). 7. Schroder W. Et al. Eur. J. Pain 2010; 14:814-821

*mu-opioid receptor agonists also activate the inhibitory descending pain pathway at a supraspinal level, however their efficacy in chronic neuropathic pain may be limited and require higher doses than for nociceptive pain4-6

†Animal data do not necessarily predict human clinical effect

BINDING AFFINITY & POTENCY AT BINDING AFFINITY & POTENCY AT MU-OPIOID RECEPTORMU-OPIOID RECEPTOR11

Compared to morphine:Palexia SR has 18 times less binding affinity to the human mu-opioid receptor1

But it is only 2-3 times less potent in producing analgesia (on a dose per weight basis) 1*

This low in-vivo potency difference is consistent with its 2 mechanisms of action

Refs: 1.Palexia SR Product Information, June 2013.

* Animal data does not necessary predict human clinical effect

SUMMARY: PALEXIA SRSUMMARY: PALEXIA SR®®

1. Schroder W et al. JPET 2011; 337:312-320 2. Tzschentke T et al. JPET 2007; 323:265-2763. Palexia SR Product Information, June 2013. 4. Kress HG. Eur J Pain 2010;14(8):781-3 5. Argoff C. Curr Med Res Opin 2011;27(10):2019-31. 6. Lange B, et al. Advanced Therapeutics 2010;27(6):381-399. 7.Wild JE, et al. Pain Pract 2010;10(5):416-27.

• Two complementary and synergistic mechanisms, MOR and NRI, in a single molecule1,2†

• Targets both pain pathways and delivers efficacy in nociceptive, mixed and neuropathic pain3-5

• Effective as oxycodone CR in chronic moderate to severe pain6*

• Superior GI tolerability vs oxycodone CR6*

• Significantly greater improvement in 7 of 8 SF-36 health-related measures of quality of life compared with oxycodone CR6*

• Sustained relief to 1 year, with similar adverse effects to that of short-term treatment7#

† Animal data does not necessarily predict human clinical effect

*Pooled and pre-planned meta-analysis of three Phase III trials in moderate to severe chronic low back pain and osteoarthritis of the knee. All three trials were randomised, double-blind and evaluated the efficacy and tolerability of PALEXIA SR (100–250mg BD) compared with placebo and oxycodone CR 20–50mg BD) over 15 weeks. The primary objectives of the pre-planned meta-analysis were to examine whether the GI tolerability of PALEXIA SR was superior to oxycodone CR (based on lower incidence of constipation), and if shown, to assess whether the efficacy of PALEXIA SR was non-inferior to oxycodone CR (based on 50% retention of oxycodone CR effect). 1

#Randomised, open-label, active-controlled, study (n=1,117) in patients with moderate to severe knee/hip OA pain or low back pain randomised to Palexia SR (100-250 mg bd) or oxycodone CR (20-50 mg bd). Primary objective: safety of Palexia SR over 1 year.2

Schwartz 2011588 patients

Initial 3 week open label phase All patients titrated to between 100–250 mg bd over a 3

week period 60.5%, 30% improvement 34.9%, 50% improvement

12 week double blind randomsied to Tapentadol SR or placebo 64.4% improved on Tapentadol 38.4% improved on placebo (p<0.001)

TAPENTADOL SR AND DPN

CASE STUDY - MRS TM

62 year old female Working as a management consultant

20 year history of generalised body pain Neck, shoulder, hips, knees and lower back Constant dull ache with frequent sharp, stabbing and

burning pain Intermittent paraesthesia and numbness of left leg Pain frequently wakes her at night

Celebrex 200mg daily for the last 3 monthsAmitriptyline 10mg at night intermittentlyTried Pregabalin, Targin and Buprenorphine patch

CASE STUDY - MRS TM

CT scan of lumbar spine / MRI scanMultilevel degenerative disc / joint diseaseModerate spinal canal stenosis at L3/4Facet joint arthropathy L4-5 and L5/S1

Lower limb nerve conduction studiesNo evidence of peripheral nerve dysfunction

EMG studiesNo evidence of radiculopathy

CASE STUDY - MRS TM

Treatment•Celebrex 200mg mane and Amitriptyline 10mg nocte continued•Commenced on Tapentadol SR 50mg twice per day •Increased to 100mg twice a day in 2 weeks time•Home range of motion exercise program

Review 6 weeks•Complete resolution of pain (20 year history)•Constant pain resolved•Sharp, stabbing and burning pain resolved•Paraesthesia of left leg resolved•Sleeping well – stopped Amitriptyline and Celebrex

Increased Function•Vacuuming whole house without break, •Preparing food without difficulty, •Mopping floors and •Going up a 12 foot ladder to clean gutters

BOTULINUM TOXIN

Action at CNS level mediated through afferent pathways originating at muscle spindles

Effective for up to 10 - 12 weeks

3 patients with TN Up to 100 u of Botulinum Toxin (Botox) in 2 ml normal saline 50 u injected just above the zygomatic arch at a depth of 1.5 to 2 cm 20 u injected into 4-8 trigger points in V territory (2.5 u each)

Case 1 Baseline 1 mth 2 mth 3 mth 4 mth

NRS 8/10 5/10 4/10 2/10 5/10

37 year old single lady Left TN -facial (cheek) pain - April 2013

Sharp, stabbing, knife-like lasting 2-3 mins, 10 times per day

MRI scan of her brain Left superior cerebellar artery in contact with left trigeminal nerve No evidence of an underlying demyelinating illness or demyelinating plaque

Responded very well to Carbamazepine 200mg bd Intolerable side effects

Drowsiness, tiredness, dizziness, light headedness, personality change and suicidal thoughts

Pregabalin commenced – up to 150mg bd Improved symptoms by about 50%, but pain recurred – Dizzy

Oxcarbamazepine up 150mg bd Pain improved by about 90-95% Developed joint and muscle pain, flu-like symptoms, swelling of legs

Gabapentin 100mg nocte increasing to 300mg 3 times per day

MS NB

75 units of Botulinum Toxin (Botox) injected 50 units just under the left zygomatic arch 10 units into infraorbital nerve 2.5 units into 6 sites over the left V2 region, intradermally to the

sites of maximum tenderness

 Marked improvement in her pain

For about 4 weeks, her pain had improved by about 90% Constant burning sensation over her left cheek had virtually

resolved and no sharp, stabbing pain

 Left lower facial weakness as a result of Botox

Asymmetrical smile Drool from the left side of her mouth

 Recurrence of pain after 2 months

MS NB

Botulinum Toxin injections repeated 50 units upper part of her face just below her left zygomatic

arch with 10 units into infraorbital nerve 2.5 units next to her nasal cleft 2.5 units into 5 trigger points in the left V2 region NOT into orbicularis oris region

Improved her symptoms No facial weakness as orbicularis oris was not injected

Botulinum Toxin injections very effective

Improved pain by about 90%, for nearly 2 months Previously experiencing pain about 10 times per day to 1 or 2

episodes of pain a month

MS NB

VITAMIN B12VITAMIN B12

Used by the body in the production of myelin

Gross deficiencies Lead to nerve damage (pain and inflammation) Beef, lamb, eggs, liver, oysters

Parenteral B12 or oral 1000 mcg daily Methylcobalamin

Help regenerate myelin and nerve cells, even in non-deficient

Initial studies (1940’s) -promising resultsTalaei 2009

Parenteral vitamin B(12) vs nortriptyline in DPN – 100 patients Pain decreased 3.6 on NRS with vitamin B12 and 0.8 Nortriptyline

Recent study in TN also promising

VITAMIN B12VITAMIN B12WOOD & AGGARWALWOOD & AGGARWAL

Group B12 Serum level

(pgm/L)

Trigeminal Neuralgia

patients

Other Facial Pain

patients

1 <106 0 0

2 106-200 13 2

3 201 - 300 18 11

4 301 - 400 14 4

5 401 - 450 5 2

6 > 450 7 0

Total 57 19 76 patients

20% were vitamin B12 deficient (<200pg/ml)

71 % had low vitamin B12 levels (200-450pg/ml)

VERSATIS®

1 Versatis® Approved Product Information May 2012.2 Garnock-Jones KP and Keating GM. Drugs 2009: 69 (15): 2149-2165.3 Rowbotham M. et al. Pain 1996;65:39-44.

Lignocaine 5% dermal patch- neuropathic pain associated with post-herpetic neuralgia (PHN)

Dual mode of action:

PharmacologicalDiffusion into the skin – Na channel blockade, preventing ectopic discharge in dysfunctional nerve fibres

MechanicalHydogel patch – soft, soothing protective barrier over hypersensitive skin to reduce allodynia

Responder rate*, after 4 weeks of treatment (n=88)1†‡

Prolonged response to a noxious stimulusDramatic increase in duration and magnitude of cell responses, but input into the spinal cord remains the same

Activation of:Neurotransmitters (glutamate, substance P, NO)

Receptors ( NMDA) Inflammation and chemicals (neurotropin)Genes (Cfos)

WIND - UPWIND - UP

Ketamine Non-competitive NMDA antagonist Use limited by due side effects (hallucinations) Lack of oral preparation (only IV, SC and spinal).

Oral NMDA receptor antagonists Dextromethorpan, Amantadine and Memantine

Dose required for Dextromethorphan As a cough suppressant 40-80mg Pain 400mg / day

Dextromethorphan NNT for DPN2.5 (CI 1.6 - 5.4) Dextromethorphan NNH 8.8 (CI 5.6 – 21.1)

KETAMINEKETAMINE

DescriptionAverage daily ketamine infusion dose

(mg)

Lowest 201

Highest 526

Sample Average 228

AV. DAILY KETAMINE DOSEAV. DAILY KETAMINE DOSE

50ml SyringeKetamine 200mg +/- Lignocaine 2000mg (2x10x10% xylocaine) sub-cutaneously Day 1 2ml/hr ie 8mg/hr or 192mg/dayDay 2 2.5ml/hrDay 3 3ml/hrDay 4 Double Ketamine (400mg) and reduce back to

2ml/hr

KETAMINE STUDY - RPAHKETAMINE STUDY - RPAH

• Significant reduction in mean pain intensity VAS in 42/56:

•6.38 before ketamine

•4.60 after ketamine

• (p < 0.005)

VAS SCORES VAS SCORES (BEFORE / AFTER KETAMINE)(BEFORE / AFTER KETAMINE)

• There was significant reduction in opioid dose at the end of ketamine infusion with the mean morphine equivalent dose:

•216 mg/day before ketamine

•89 mg/day after ketamine

• (p < 0.005)

EQUIVALENT MORPHINE DOSE EQUIVALENT MORPHINE DOSE BEFORE / AFTER KETAMINE BEFORE / AFTER KETAMINE

EFFECT OF KETAMINE LOZENGESEFFECT OF KETAMINE LOZENGES

NO LOZENGES

LOZENGES

NEUROPATHIC PAIN – CONCLUSION

Prevalence 25-50% patients treated at Pain clinics

Complex pathophysiology Precise mechanisms unknown Multiple mechanisms involved

Under-assessed and under-treated

Available treatments provide only modest reduction of pain

CUSTOMISING TREATMENT The search for pain management