Dr J C D Wells Pain Research Institute,

Liverpool, UK President Elect, EFIC

Founder and honorary member of NeuPSIG Treasurer, WSPC Councillor, WIP

Pain Relief Foundation

Liverpool

E’un grande onore per affrontare l’incontro piu importante il trattamento del dolore a

Italia quest’anno

Neuropathic Pain : a wide variety of Aetiologies

Shingles

Surgery Radiculopathy Trauma

Syringomyelia

Pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP, 1994)

Definitions

Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al.,Neurology 2008)

Pain quality, mixed pain, not taken into account

Both types of pain co- exist in

many conditions (mixed pain)

Neuropathic pain

Nociceptive pain

Webster LR. Am J Manag Care 2008;14 (5 Suppl 1):S116–22 Ross E. Expert Opin Pharmacother 2001;2:1529–30

Freynhagen R, Baron R. Curr Pain Headache Rep 2009;13:185–90

Lumbar vertebra

Disc herniation

Activation of peripheral nociceptors –cause of nociceptive pain component1

Compression and inflammation of nerve root – cause of neuropathic pain component2

1. Brisby H. J Bone Joint Surg Am 2006;88 (Suppl 2):68–71 2. Freynhagen R, Baron R. Curr Pain Headache Rep 2009;13:185–90

Lesion

Activation of local

nociceptors1

Constant ache, throbbing pain in the low back2

Patient presents with both types

of pain

Shooting, burning pain in the foot2,3

Ectopic discharges from nerve root lesion2

1. Brisby H. J Bone Joint Surg Am 2006;88 (Suppl 2):68–71 2. McMahon SB and Koltzenburg M. Wall and Melzack’s Textbook of Pain. 5th ed. London: Elsevier; 2006; pg 1032 3. Freynhagen R, Baron R. Curr Pain Headache Rep 2009;13:185–90

¨ “Pain can be more or less neuropathic” Rasmussen et al, 2004; Attal and Bouhassira, 2004; Bennett et al 2006

¡ Gradient of neuropathic characteristics with increasing diagnostic certainty (MPQ, NPS, DN4, S-LANSS)

¨ So neuropathic pain can be seen as a spectrum, not a dichotomy

¨ Which point on the spectrum do we use for epidemiological case definition?

¨ Common features among all causes ¡ Mechanisms, symptoms, signs ¡ HRQoL impact more dependent on intensity than cause Doth et al 2010

¨ Common response to some treatments ¡ Sindrup and Jensen, 1999; Hansson and Dickenson, 2005

¨ Not always possible to distinguish diagnosis ¡ Especially in primary care, also in epidemiology (eg ca, local)

¨ Specific treatments available for NeuP? ¡ Therefore important to try identify and target unclassified and

mixed cases, as well as classical syndromes ¡ Daniel et al (2008) – different treatment needs for NeuP than for

CLBP

¨ Obvious aetiological differences ¡ Eg, PDN, PHN, Postsurgical pain, central pain, HIV neuropathy

¨ With implications for prevention ¡ Eg treating hyperglycaemia, HZV immunisation, HIV prevention

¨ Emerging evidence of clinical differences ¡ Fields et al 1998: two distinct PHN subtypes ¡ Baron et al 2009: five distinct NeuP subtypes, frequencies vary in PHN and LBP ¡ Grémau-Richard et al 2010: different response to treatment in 2 BMS subtypes ¡ ?implications for treatment generally

¨ Most RCTs are condition-specific ¡ Evidence limited of application to different conditions ¡ Some evidence of condition-specific effects, eg HIV ú Amitriptyline and gabapentin ineffective (Kieburtz et al 1998; Hahn et al 2004; Shay et al 1998) ú Cannabis effective (Abrams et al 2007; Ellis et al 2008)

¨ Condition-specific estimates ¨ Prevalence of neuropathic pain ~1% Bowsher 1990

¨ Prevalence of neuropathic pain ~2% Bennett 1997

¨ “Thought to be more common than has been

generally appreciated…” Dworkin 2002

¨ S-LANSS Torrance et al 2006; Smith et al 2007

¡ “Pain of predominantly neuropathic origin” ¡ 8.2% (UK)

¨ DN4 Bouhassira et al 2008

¡ “Pain with neuropathic characteristics” ¡ 6.9% (France)

¨ Validated in pain clinic populations ¨ Validity and PPV unknown in general population

Therefore, this is not the prevalence of neuropathic pain Prevalence of “possible neuropathic pain? Treede et al 2008

¨ PHN ¡ Prevalence 2.6% to 10% of those who have had HZ ¡ Higher in older age-groups

¨ PDN ¡ Prevalence 8% to 20% of those with Type 2 diabetes

¨ Back pain neuropathy ¡ Prevalence 37% of those with CLBP (painDETECT) ¡ Population prevalence 0.75% to 14.5% !

¨ Poor health-related quality of life Schmader et al 2002; Smith et al 2007; Jensen et al 2007; Doth et al 2010

¨ HRQoL most dependent on pain intensity Doth et al 2010

¨ HRQoL scores equivalent to those found in ¡ Clinical depression ¡ Coronary artery disease ¡ Recent MI ¡ Poorly controlled diabetes

¨ Increasing impact on society ¡ Ageing population ¡ Increasing prevalence of DM ¡ Global burden of HIV (33.2 million have HIV; 35% have painful

neuropathy)

Patients with ‘moderate’ to ‘very severe’ discomfort (n=126)

40 20 70 60 0 50 30 10 Patients (%)

Difficulty sleeping

Lack of energy

Drowsiness

Difficulty concentrating

Depression

Anxiety

Poor appetite

Type

of f

unct

iona

l im

pairm

ent

Adapted from Meyer-Rosberg et al. Eur J Pain 2001;5:379–89 06-00306 Date of preparation March 2010

Pain In Practice - A medical education meeting initiated and funded by Pfizer

Available epidemiological evidence confirms that: ¨ Neuropathic pain is common ¨ Neuropathic pain is important, cost + QOL ¡ To individuals ¡ To society

¨ There is potential to target identification and treatment strategies

¨ There are opportunities for prevention ¨ More research is needed

Holistic Psychological Pharmacological Interventional (NeuPSIG guidelines for H+I)

0

10

20

30

40

50

60

70

80

ParacetamolNSAIDsAntidepressantsOpioidsAEDsAspirin

NSAIDs, non-steroidal anti-inflammatory drugs; AEDs, anti-epileptic drugs Adapted from Hans G et al. BMC Public Health 2007;7:170

Patie

nts

pres

crib

ed tr

eatm

ents

fo

r neu

ropa

thic

pai

n (%

)

Graph adapted from an observational study looking at neuropathic pain in daily practice in Belgium

*

*

* * Some Antidepressants, AEDS & Opioids have demonstrated efficacy.

PNS

C fibre

Ab fibre

Lesion

Phenotypic changes

Ectopic discharges

Ectopic discharges

Phenotypic changes Gene dysregulation

glutamate peptides

SP?

Alteration of inhibitory controls

Hyperexci- tability of nociceptive neurons

Neuropathic pain

Reduction of segmental inhibition GABA, KCC2, glycine

Microglial activation

CNS

In: Bouhassira and Attal, douleurs neuropathiques, 2007

PNS CNS

Gene regulation

Current therapeutic targets

Desensitization

Excitability

Central sensitization

Inhibition of the transmission

Segmental inhibition

Descending controls

Microglial activation

Alpha2delta agonists (gabapentin, pregabalin)

Antidepressants Alpha2delta agonists Opioids/tramadol

Tricyclic antidepressants Sodium channel blockers - Lidocaine - Antiepileptics

Opioids

Alpha2delta agonists (gabapentin, pregabalin)

Meta-analysis of neuropathic pain treatments

Finnerup et al. Pain 2005 NNT 50% pain relief

0 2 4 6 8 10 12

Topiramate SSRI

Capsaicin NMDA antagonists

Mexiletine

SRNI

Gabapentin / Pregabalin Tramadol

Opioids

Carbamazepine / Lamotrigine

Valproate

TCAs 397

389

120

420

1057

81

466

150

214

149

109

83

Peripheral NP

Adapted from C. Wells and G. Mick (with permission)

Finnerup et al 2005 Pain Current update

Attal et al 2006, 2010 Eur J Neurol

Gilron et al 2006 CMAJ

Dworkin et al 2007 Pain Summary of recommendations Mayo Clin Proc 2010

Treatment algorithm based on meta-analysis

EFNS guidelines (aetiology-based)

Practical guide Consensus based NeuPsig recommendations

131 refs 147 refs 138 refs 132 refs

Algorithm for peripheral neuropathic pain treatment: an evidence based proposal

Lidocaine plaster*

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

Aetiology Recommendations for first line

Recommendations for Second / third line

Diabetic NP PHN Central NP

Duloxetine 60-120 mg/d Gabapentin 1200-3600 mg/d Pregabalin 300-600 mg/d TCA 25-150 mg/d Venlafaxine ER 150-225 mg/d Gabapentin Pregabalin TCA Lidocaine plasters 1 to 3/day Gabapentin Pregabalin TCA

Opioids (individual titration) Tramadol 200-400 mg/d Capsaicin cream 4 appl./day Opioids Lamotrigine 200-400 mg/day Opioids Tramadol (SCI)

Attal et al. Eur J Neurol 2010

EFNS guidelines

PHN with allodynia*

Lidocaine patches

Peripheral neuropathic pain

GBP/pregabalin TCA/SNRI**

Attal, et al EFNS guidelines Eur. J Neurol, 2010

No effect Side effects

Opioids Tramadol

NeuPsig recommendations

Dworkin et al Pain 2007

- Antidepressants (TCA/SNRI) - Gabapentin or pregabalin - Topical lidocaine (localized pain) - Opioids or tramadol (acute NP, cancer NP or episodic exacerbations of severe pain and when prompt pain relief is required)

* Particularly in the elderly ** first line in painful polyneuropathies

Moore et al. Cochrane database of Systematic Reviews 2009

Fibromyalgia

PDN

Central NP

PHN

1 2 4 6 8 10 12 14 16 18NNT (95% CI): at least 30% pain improvement at 12 weeks

Pregabalin in neuropathic pain

Pregabalin 600 mg daily moderate benefit or better at study end

Sultan et al. BMC Neurology 2008;8:29 Moore et al. Cochrane database of Systematic Reviews 2009

Moore et al, unpublished

Pregabalin 450/600 mg

Duloxetine 60/120 mg

Tramadol/acetaminophen 300/2600 mg

Amitriptyline 25/50 mg

1 2 4 6 8 10 12 14 16NNT for at least moderate benefit at 12 weeks (95% CI)

Fibromyalgia pain moderate benefit or better at study end

CLBP

Osteoarthritis

Fibromyalgia

PDN

1 2 4 6 8 10 12 14 16 18NNT (95% CI): at least 30% pain improvement at 12 weeks

Duloxetine in chronic pain

Duloxetine 60/120 mg daily

Various sources

moderate benefit or better at study end

Antidepressant Outcome Trials Patients Placebo Active NNT (95% CI)

Duloxetine 60/120 mg at least 50% pain relief 3 1024 27 47 5.1 (3.9 to 7.3)

Amitriptyline all doses global improvement 10 588 32 64 3.2 (2.6 to 4.2)

Other antidepressants global improvement 3 216 12 50 2.6 (2.0 to 3.7)

Venlafaxine all doses global improvement 3 200 25 57 3.1 (2.2 to 5.1)

Desipramine all doses global improvement 2 78 10 59 2.1 (1.5 to 3.3)

Imipramine all doses global improvement 2 58 5 97 1.1 (1.0 to 1.2)

Number of Percent with

Sultan et al. BMC Neurology 2008 8:29.

Sultan et al. BMC Neurology 2008;8:29 Moore et al. Cochrane database of Systematic Reviews 2009

Pregabalin 600 mg

Pregabalin 300 mg

Duloxetine 60/120 mg

Pregabalin 600 mg

Pregabalin 300 mg

Duloxetine 60/120 mg

1 2 4 6 8 10 12 14 16 18NNT (95% CI): pain improvement at 12 weeks

Moderate benefit

Substantial benefit

Painful diabetic neuropathy IMMPACT outcomes or better at study end

¨ CNP arises from damage to ascending spino-thalamo-cortical pathways, their relays, or end-stations in the spinal cord or brain.

¨ Usually a pain in an area of altered sensation

“pain arising as a direct consequence of a lesion or

disease affecting the somatosensory system” Treede et al, 2007

Same general principles as all NPP Worse results! Little clinical trial work ? small numbers ? –ve outcomes ? lack of interest

PNPP 76/101 +ve trials 68.5% CNPP 4/9 +ve trials 44.4%

in small trials only:-

TCA’s (Amit) ( Rintala) Gabapentin ( To, Siddall ) Pregabalin (Vranken, Siddall) Carbamazepine (Leijon, CPSP) Opioids (iv) (Attal) Lamotrigine (Vestergaard, Finnerup) Topiramate (Harden) Tramadol ( CNP) Cannabinoids ( Rog, Svendson,in MS) IV lignocaine (then carbamazepine?) Ketamine ( Eide, iv only)

Amitriptylene ( Cardenas ) Opioids Mexiletine Ketamine Lozenges Baclofen Valproate Trazodone

Agents Outcome

Amitriptyline vs acupuncture Negative Amitriptyline vs mexiletine Negative

Lidocaine gel Negative Lidocaine patch Insufficient data

Lamotrigine Pain improved/-ve Gabapentin Pain improved/-ve Pregabalin Negative

Capsaicin patch (high conc.) Pain improved Cannabis (smoked) Pain improved

Duloxetine/Methadone +ve and -ve

Agents Outcome

Peptide T No effect Prosaptide No effect

Nerve growth factor Pain improved; No regeneration

L-Acetyl carnitine No effect Erythropoetin Failed accrual

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

N=196 Duration

16 17

24

43

0

5

10

15

20

25

30

35

40

45

50

3 to 6 7 to 12 13 to 35 36+ Months

% P

atie

nts

moderate

severe mild

unclear

27%

46%

27%

>70

Neuropathic Pain – Unmet Needs

Pain intensity despite medication

¨ Perform rationale combination therapy

¨ Take into account psychological comorbidities

¨ Develop new compounds with lower side effect profile or acting on new targets

¨ Identify responder profiles to drug treatments based on a detailed phenotypic assessment

· G/PG upregulates spinal cord κ and m receptors1

· Oxycodone acts at κ receptors that increases anti-nociception via m receptors2

· Anecdotal evidence suggests oxycodone and G/PG may have an additive effect

· G/PG and oxycodone are already used in combination in clinical practice

· Benefit with less side effects

1.Shimoyama M et al. Pain 1997; 72: 375–82 2.Khotib J et al. Neuropharmacology 2004; 46: 531–40

Combination therapy • Gabapentin + morphine > gabapentin or morphine monotherapy

in diabetic NP and PHN (level A) – Gilron et al. NEJM 2005

• Gabapentin + nortriptyline > gabapentin or nortriptyline monotherapy in diabetic NP and PHN (level A)

– Gilron et al. Lancet 2009

• Gabapentin + venlafaxine > gabapentin monotherapy in diabetic NP (level B)

– Simpson et al. J Clin Neuromusc disease 2001

• Negative trial in radiculopathy with morphine + nortriptyline combination (level B)

– Khoromi et al. Pain 2007

0

1

2

3

4

5

6

7

Bas

elin

e

Plac

ebo

GB

T

Mor

phin

e

GB

T/m

orph

ine

Pain

inte

nsity

sco

re

Gilron I et al. NEJM 2005; 352: 1324–34

Psychological comorbidities

•Psychological comorbidities frequent in chronic NP (Turk et al Mayo Clin Proc 2010; 85: S42-50)

•Importance of pain coping strategies and catastrophizing in pain chronicity

(Haythorthwaite et al Pain 2003; 106: 453-460; Sullivan et al Pain 2009; 143: 123-129)

•Role of catastrophizing in therapeutic outcome in NP ?

PNS CNS Gene regulation Neurotrophins Anti-NGF

Develop new compounds

Excitability Nav channel blocker Ralfinamide Potassium openers Retigabine

Central sensitization AMPA antagonists Terampanel mGlutamate inhibitors Calcium channel blockers Ziconotide (Prialt) (IT) Novel alpha2delta agonists

Inhibition of transmission Cannabinoid receptor agonists Sativex

Segmental inhibition GABA agonists

Modulatory controls New opioid and NE reuptake inhibitors Tapentadol Cannabinoid receptor agonists Sativex Nicotinic agonists

Microglial activation Cytokine inhibitors MAPK inhibitors

Desensitization Neurogenic inflammation Botulinum toxin A TRTPV1 agonists Capsaicin patches

Botulinum toxin inhibits Ach release at the neuromuscular junction

Synaptic junction

Ach vesicle Exocytosis

Muscular fiber

Slide: D. Ranoux

l Analgesic effects in dystonia (Tsui 1986, Brin 1987)

– Early analgesic effect before the antidystonic effect – More important than would be expected from the effect on

hypertonia l Effects on chronic migraine (Picket Biodrugs 2010)

l Several anecdotical reports of effects on neuropathic pain or trigeminal neuralgia

(eg, Yoon et al Pain Med 2010) l Sustained antiallodynic effects on animal models of

neuropathy (Bach-Rojecky et al E J Pharmacol 2010; Luvisetto et al Neuroscience 2007; Favre-

Guimard et al E J Pharmacol 2009 )

Botulinum toxin A and neuropathic pain Rationale

Purkiss et al Biochem Pharmacol 2000 Durham et al Headache 2004

Botulinum toxin A blocks vanilloid receptor activity

Botulinum toxin A reduces Substance P, CGRP release from DRG neurons or nociceptors

Morenilla-Palao J Biol Chem 2004

Botulinum toxin A may reduce capsaicin-evoked pain in human skin

Tugnoli et al Pain 2008 Gazerani et al Pain 2006, 2009 See however Voller et al Neurology 2003 and Schulte-Malter et al J Neurol Sci 2007

BTXA

saline

Effects on neurogenic inflammation

¨ Peptide mediated transdermal delivery (Carmichael et al Pain 2010) • Recombinant chimera of BoNT/A and BoNT/E (Meng et al J Neuroscience 2009) • Re-engineering of Botulinum toxins that target nociceptive

neurons - modified clostridial endopeptidase - Drug delivery using a clostridial neurotoxin-based vehicle (Picket, Biodrugs 2010)

PNS CNS Gene regulation Neurotrophins: GDNF Anti-NGF

Develop new compounds

Desensitization Neurogenic inflammation Botulinum toxin A TRTPV1 agonists Capsaicin patches

Excitability Nav channel blocker Ralfinamide Potassium openers Retigabine

Central sensitization AMPA antagonists Terampanel mGlutamate inhibitors Calcium channel blockers Ziconotide (Prialt) (IT) Novel alpha2delta agonists

Inhibition of transmission Cannabinoid receptor agonists Sativex

Segmental inhibition GABA agonists

Modulatory controls New opioid and NE reuptake inhibitors Tapentadol Cannabinoid receptor agonists Sativex Nicotinic agonists

Microglial activation Cytokine inhibitors MAPK inhibitors

Lidocaine Patch 5%

C

Capsaicin 8%

•Active ingredient in chili peppers

•Known receptor: VR1

•Respond to heat stimuli

•Pain

•Acidic environment

•Available in a topical cream (max conc 0.075% )

•Exptal hi-conc patch

• (8%, Qutenza®)

Kennedy WR, et al. J Pain 2010 Apr 16 [Epub ahead of print]

DN=dermal fibre; DEJ=dermal-epidermal junction; ENF=epidermal nerve fibre

Week 1 Qutenza Week 1 Control

Capsaicin: Application Procedure

Courtesy of R. Baron

Who are the best responders to capsaicin ?

ÿ No specific assessment of NP symptoms (eg, burning, pain paroxysms, deep pain, evoked pain) ÿ Best potential responders would be patients with mechanical/thermal allodynia and weak thermal deficits (ie, clusters 1 and 4 from Baron et al Pain 2009)

Mean (SE) % Change from Baseline Diary Score for Average Pain in Past 24 Hours

Pooled data from the 30-, 60-, and 90-minute application times are shown.

% C

hang

e fr

om B

asel

ine

-30

-20

-10

0

0 1 2 3 4 5 6 7 8 9 10 11 12 Post-Treatment Week

* † ‡ ‡ † † † † † † P=0.006

* P<0.05, †P≤0.01, ‡P≤0.001 Control NGX-4010

Simpson D, et al. Neurology 2008; 2008;70:2305-2313

% Patients with ³30% Pain Decrease from Baseline to Weeks 2-12

Pooled data from the 30-, 60-, and 90-minute application times are shown.

% P

atie

nts

Control NGX-4010

10

20

30

40

50

18% 34%

P=0.009

18% n=82

34% n=225

Finnerup et al. Pain 2005

Capsaicin and neuropathic pain

NNT 50% pain relief 0 2 4 6 8 10 12

Topiramate SSRI

Capsaicin NMDA antagonists

Mexiletine SRNI

Gabapentin / Pregabalin Tramadol

Opioids Carbamazepine / Lamotrigine

Valproate TCAs 397

389

120

420

1057

81

466

150

214

149

109

83

NNT 7

Rog et al (2005) +ve results for Sativex Spray Svendson et al, Dronabinol in MS Improvement in sleep Reduction in pain Well tolerated

Recent +ve trial for spasticity in MS (doubled share price for GW Pharma)

¨ Smoked cannabis (3.96% Δ9-THC) vs placebo cigs; 3x/d x 5d

¨ N = 50; parallel gp ¨ Pain ¯: Can: 34%, plac:

17% (p = .03) ¨ ≥ 30% pain ¯: Can:

52%, plac: 17% (p= .04) ¨ AE ­ with can: anxiety,

sedation, dizziness, confusion

Abrams et al. Neurol 2007;68:515-521

Campbell F et al., Are Cannabinoids an effective and safe Treatment Option in the Management of Pain? A qualitative, systematic Review.

BMJ 2001; 323:13–16

¨ Systematic review of cannabinoid derivatives tested in cancer, chronic non-malignant and post-operative pain

¨ Cannabinoids no more effective than codeine in controlling pain

¨ Adverse effects [eg CNS depression,] limit their use

Concluded: “ Their (cannabinoids) widespread introduction into clinical practice for pain management is therefore undesirable”

¨ Good in theory ¨ Variable in practice (conflicting views) ¨ No evidence of Ketamine benefit in trial work ¨ Memantine, Amantadine, no +ve work yet. ¨ Opioids with NMDA antagonism?

(methadone, dextromethorphan)

X

a2-R

NA

Descending pathway from the brain

+ SP

Glut

Ascending pathway to the brain

Pain signal ---

+ MOR

Tapentadol

MOR

Spinal cord mechanisms of action

Tzschentke TM et al. J Pharmacol Exp Ther 2007 Vol 323(1): 265-76 Tzschentke TM et al. Drugs Today 2009 Vol 45(7): 483-96

05

10152025303540

Nause

a

Vomitin

g

Const

ipatio

n

Dizzine

ss

Somno

lence

Prurit

us

%

Placebo n=1498

Tapentadol SR n= 3613

Oxycodone CR n= 1472

Data on file

TEAE in ≥ 5% patients Numerical differences only

Algorithm for peripheral neuropathic pain treatment: an evidence based proposal

Lidocaine plaster Capsaicin patch*

TCA (SNRI)

Gabapentin/ Pregabalin

Gabapentin/ Pregabalin

Postherpetic neuralgia and focal neuropathy, allodynia

Peripheral neuropathic pain

yes

TCA (SNRI)

yes

Tramadol, Tapentadol, Oxycodone

TCA contraindication

no yes TCA contra-indication

no

no

¨ Prevention of stroke ¨ better acute management of stroke ¨ SCI , reduction of trauma ¨ SCI, better initial treatment ¨ Acute shingles, reduction, treatment ¨ Diabetic PN, better control of glucose levels ¨ Better Rx of HIV, AIDS

CPSP prevention of strokes lipid reduction, statins blood thinners, aspirin, clopidogrel promotion of active lifestyle reduction of obesity Acute Stroke Management thrombolytics, etc Prophylactic early treatment Brain Derived Neurotrophic Factor TCA’s, Anticonvulsants

In general, promote a fitter, healthier, lifestyle Prevention and treatment of Obesity (CPSP,

Diabetes) Encouragement of Fitness Healthy Habits, ( smoking, veg + fruit) Genetic Manipulation Gene Therapy

¨ More common than previously appreciated ¨ Careful assessment required ¨ Clear treatment algorythyms ¨ Multidisciplinary approach required ¨ Still major deficiencies in success ¨ Need for better treatments with less side effects ¨ Need for better health measures in future

A critical look at new and existing treatments for pain: Back Pain, Neuropathic Pain and Cancer Pain Kenes, WSPC