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NEUROPATHIC PAIN
MEDICATION
UPDATE: 2015
A/Professor Arun Aggarwal
Royal Prince Alfred Hospital
Pain Management Centre
SYDNEY AUSTRALIA
International Conference on
Pain Medicine 2015 – Chicago
DISCLOSURES
Professor Aggarwal is on medical
advisory boards, received
sponsorship or honoraria from the
following companies:
BioCSL
Hospira
iNova
Mundipharma
Pfizer
UCB
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
Patient
Education
e.g. knowledge
about pain,
realistic goals
Psychological
Therapies
e.g.
counselling,
treatment of
depression
Pharmacological
treatment
e.g. NSAIDs, opioids,
adjuvants
e.g.
physiotherapy
,
exercises/stre
tches, TENS
Interventional
Therapy
e.g. procedures,
surgery
1.
Pergolizzi J. Curr Med Res Opin 2013;29(9):1127-1135.
Physical
Therapies
T H E MA J O RIT Y O F PA T I ENTS ( 1 0 8 4 ) I N 2 0 0 7
PR E S CRI BE D D R U GS WIT H NO D E MO NST RAT ED
EF F IC ACY I N NE U R OPATHIC PA I N
*
Patients prescribed treatments
for neuropathic pain (%)
AEDS, some antidepressants, and
opioids have demonstrated efficacy in
neuropathic pain
*
*
*
*
*
*
Graph adapted from a Belgian observational study of neuropathic pain treatment in daily practice 1084 patients
PHARMACOTHERAPY
 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
NNT’S FOR DIABETIC
PERIPHERAL NEUROPATHY
 Carbamazepine
 Amitriptyline
2.3
2.4
(CI 1.6 - 3.8)
(CI 2.4 – 4.0)
 Dextromethophan2.5
 Gabapentin
3.8
(CI 1.6 - 5.4)
(CI 3.5 - 5.7)
 Tramadol
3.9
(CI 2.7 - 6.3)
 Lamotrigine
4.0
(CI 2.1 - 4.2)
 Pregabalin
 Topiramate
4.2
7.4
(CI 3.9 – 6.6)
(CI 4.3 – 28.5)
NNH’S FOR DIABETIC
PERIPHERAL NEUROPATHY
 NNH - major harm not statistically
significant for any drug compared to placebo
 Carbamazepine
 Amitriptyline
 Gabapentin
3.7 (CI 2.4 - 7.8)
3.7 (CI 2.9 - 5.2)
3.5 (CI 2.0 - 3.2)
 Opioids
 Topiramate
 Pregabalin
4.2 (CI 3.2 - 5.6)
6.3 (CI 5.1 - 8.1)
6.5 (CI 4.0 – 8.3)
DOSAGE AND DURATION
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
WHO ANALGESIC LADDER
AUSTRALIA 2015 (NOCICEPTIVE)
Supervised
Symptoms
Severe
Strong opioids (oxycodone, tapendatol, Targin,
morphine, fentanyl)
for moderate-severe pain
+/- non opioids +/- adjuvants
Persistent pain or increasing pain
Weak opioids (codeine, tramadol*, buprenorphine)
for mild-moderate pain
+/- non opioids +/- adjuvants (TCA#, AED^)
Persistent pain or increasing pain
Non-opioids (paracetamol, NSAID’s, COX-2)
* TGA indicated for moderate to severe pain; ^pregabalin is TGA indicated for neuropathic pain; #not TGA-indicated for pain management
Mild
NEUROPATHIC PAIN THERAPIES
AUSTALIA 2015 ( A G G A R W A L )
 Anti-Convulsants
Carbamazepine, Oxcarbazepine
Valproate, Phenytoin
Gabapentin, Pregabalin,
Lamotrigine, Topiramate, Levetiracetam, Tiagabine
Lacosamide (Vimpat), Zonisamide
Clonazepam
 Anti-Depressants
Amitriptyline, Nortriptyline, Imipramine
Duloxetine
 Opioids
Tramadol, 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
RATIONAL POLYTHERAPY
Retigabine
Eslicarbazepine
Antiepileptic
drugs
Lacosamide
Rufinamide
Pregabalin
20
Stiripentol
Levetiracetam
Oxcarbazepine
Tiagabine
15
Topiramate
Felbamate
Zonisamide
10
Fosphenytoin
Gabapentin
Lamotrigine
Vigabatrin
Sodium Valproate
Carbamazepine
Ethosuximide
5
Phenobarbital
Phenytoin
Benzodiazepines
Primidone
Bromide
0
1840
1860
1880
1900
1920
1940
Calendar year
1960
1980
2000
15
A U S TRALIAN PA I N S O C I E TY ( A PS ) 2 0 0 8
R E C O MMENDAT IONS
F O R T H E PH A RMAC OLOGI C MA NA GEME NT O F NP
APS-preferred medications available in Australia for
treatment of neuropathic pain conditions*
Noradrenergic
antidepressants
Calcium channel alpha
2-delta ligands
Sodium channel blockers
Opioid agonist
Partial opioid agonist
/monaminergic
Nortriptylinea, amitriptylinea,
venlafaxinea, duloxetinea
Gabapentin, pregabalin
Topical lignocainea
Morphine, oxycodone, methadone
Tramadol
a
* Non-prioritised
Nortriptyline, 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
NP, neuropathic pain
SODIUM VALPROATE
 Better tolerated than Carbamazepine
 Only 1 small clinical trial in pain
 89 patients – NNT 2.3
 Increases activity
transmitter GABA
of
the
inhibitory
 t ½ 8-12 hrs
 200mg nocte increasing to 400mg bd
 SE: GIT, weight gain, tremor
 Hepatic dysfunction
 Monitor LFT’s
MRS LT
 57 yo
Left TN affecting upper jaw since 2006
 Sharp, stabbing
 Increased by chewing, eating and brushing teeth
 Since May 2009, constant burning sensation lower
jaw
 Dental procedures
 No improvement
 Carbamazepine
 Improved pain, but cognitive side effects
 Pregabalin
 Headaches
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)
STEREOISOMERS OF
VALNOCTAMIDE (VCD) K A U F M A N N 2 0 1 0
 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
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 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 1 st 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 (PALEXIA ® ) SR:
MECHANISM OF ACTION †
(COMPLEMENTARY AND INTERACT SYNERGISTICALLY)
†Animal data do not necessarily
predict human clinical effect
*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
f o r n o c i c e p t i v e p a i n 4-6
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
BINDING AFFINITY & POTENCY AT
MU-OPIOID RECEPTOR 1
Compared to morphine:
 Palexia SR has 18 times
less binding affinity to
the human mu -opioid
receptor 1
 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
* Animal data does not necessary predict human clinical effect
Refs: 1.Palexia SR Product Information, June 2013.
SUMMARY: PALEXIA SR ®
• 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 preplanned 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
1. Schroder W et al. JPET 2011; 337:312-320 2. Tzschentke T et al. JPET 2007; 323:265-276
3. 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.
TAPENTADOL SR AND DPN
 Schwartz 2011
 588 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)
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 months
 Amitriptyline 10mg at night intermittently
 Tried Pregabalin, Targin and Buprenorphine patch
CASE STUDY - MRS TM
 CT scan of lumbar spine / MRI scan
 Multilevel degenerative disc / joint disease
 Moderate spinal canal stenosis at L3/4
 Facet joint arthropathy L4-5 and L5/S1
 Lower limb nerve conduction studies
 No evidence of peripheral nerve dysfunction
 EMG studies
 No 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
4/10
2/10
5/10
5/10
MS NB
 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 Carbamazep ine 200mg bd
 Intolerable side effects
 Drowsiness, tiredness, dizziness, light headedness, personality change and
suicidal thoughts
 Pregabal in commenced – up to 150mg bd
 Improved symptoms by about 50%, but pain recurred – Dizzy
 Oxcarbamazep ine 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
VITAMIN 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 results
 Talaei 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 B12
WOOD & AGGARWAL
Group
B12 Serum level
Trigeminal Neuralgia
Other Facial Pain
(pgm/L)
patients
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
57
19
Total
76 patients
20% were vitamin B12 deficient (<200pg/ml)
71 % had low vitamin B12 levels (200-450pg/ml)
VERSATIS ®
Lignocaine 5% dermal patchneuropathic pain associated with postherpetic neuralgia (PHN)
Dual mode of action:
Pharmacological
Diffusion into the skin – Na channel
blockade, preventing ectopic discharge
in dysfunctional nerve fibres
Responder rate*, after 4 weeks of treatment (n=88)1†‡
Mechanical
Hydogel patch – soft, soothing
protective barrier over hypersensitive
skin to reduce allodynia
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.
WIND - UP
 Prolonged response to a noxious stimulus
 Dramatic 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)
KETAMINE
 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)
AV. DAILY KETAMINE DOSE
Average daily ketamine infusion dose
(mg)
Description
Lowest
201
Highest
526
Sample Average
228
50ml Syringe
Ketamine 200mg +/- Lignocaine 2000mg (2x10x10%
xylocaine) sub-cutaneously
Day
Day
Day
Day
1
2
3
4
2ml/hr ie 8mg/hr or 192mg/day
2.5ml/hr
3ml/hr
Double Ketamine (400mg) and reduce back to
2ml/hr
KETAMINE STUDY - RPAH
Post herpetic neuralgia
3%
Peripheral neuropathy
secondary to diabetes
4%
Radiculopathy
4%
Other Chronic
Neuropathic Pain
Syndrome
3%
Fibromyalgia
2%
Other Other, including Metabolic Bone
9% Disease, Phantom pain, Retinopathy,
Pancreatitis, Visceral, MS, Mastocytosis,
TMJD & Vulvodynia (each 1%)
Chronic Lumbar Spinal
Pain
41%
Idiopathic
5%
Trigiminal Neuralgia
8%
Migraine
8%
CRPS
13%
PAIN LOCATION
VAS SCORES
(BEFORE / AFTER KETAMINE)
• Significant reduction in mean pain intensity VAS in
42/56:
• 6.38 before ketamine
• 4.60 after ketamine
• (p < 0.005)
EQUIVALENT MORPHINE DOSE
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)
EFFECT OF KETAMINE
LOZENGES
No
change
in opioid
or
analgesic
use
61%
Complete
cessation
of opioids
6%
Increase
in opioid
use
11%
Reductio
n in
opioid
use
22%
No
change in
opioid or
analgesic
use
61%
Complete
cessation
of opioids
31%
Increase
in opioid
use
0%
Reduction
in opioid
use
8%
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