NEUROLOGICAL COMPLICATIONS OF DIABETES AND TREATMENT OF

NEUROPATHIC PAIN

Dwight Moulin MDDwight Moulin MD

Depts of CNS and OncologyDepts of CNS and Oncology

UWOUWO

Disclosure StatementDisclosure Statement

I have had a professional association with I have had a professional association with the following organizationsthe following organizations

Pfizer CanadaPfizer Canada

Purdue PharmaPurdue Pharma

Janssen-OrthoJanssen-Ortho

BayerBayer

Neurological Complications of Neurological Complications of Diabetes MellitusDiabetes Mellitus

CNS - metabolicCNS - metabolic

- cerebrovascular disease- cerebrovascular disease

PNS - focalPNS - focal

- generalized- generalized

Diabetic NeuropathiesDiabetic Neuropathies

Focal - abrupt in onsetFocal - abrupt in onset - severe pain- severe pain - resolve spontaneously in- resolve spontaneously in months to 1 to 2 yearsmonths to 1 to 2 years Generalized - insidious in onsetGeneralized - insidious in onset - initially painless- initially painless - progressive- progressive

Focal Diabetic NeuropathiesFocal Diabetic Neuropathies

Ocular palsies – 3Ocular palsies – 3rdrd// 6 6thth nerves nervesBrachial plexopathyBrachial plexopathyThoracic (truncal) radiculopathyThoracic (truncal) radiculopathyLumbosacral plexopathyLumbosacral plexopathyEntrapment neuropathiesEntrapment neuropathies

Generalized Diabetic Generalized Diabetic NeuropathyNeuropathy

Distal sensori-motor neuropathyDistal sensori-motor neuropathy

Autonomic neuropathyAutonomic neuropathy

Knee ReflexKnee Reflex

Dermatomes – Lower ExtremitiesDermatomes – Lower Extremities

PAINFUL DIABETIC NEUROPATHY

Diabetes MellitusDiabetes Mellitus

Diabetic NeuropathyDiabetic Neuropathy

Painful Diabetic NeuropathyPainful Diabetic Neuropathy

50%50%

10%10%

CLINICAL FEATURES OF NEUROPATHIC PAIN

Dysesthetic burning painDysesthetic burning pain

Paroxysmal lancinating painParoxysmal lancinating pain

Touch-evoked pain (allodynia)Touch-evoked pain (allodynia)

ADVANCES IN NEUROPATHIC PAIN FIRST-LINE MEDICATIONS

(Class I Evidence)

Gabapentin/PregabalinGabapentin/PregabalinTCAs/SNRIsTCAs/SNRIs5% Lidocaine Patch5% Lidocaine PatchTramadolTramadolOpioid AnalgesicsOpioid Analgesics

Dworkin et al Archives of Neurology 2003Dworkin et al Archives of Neurology 2003Gilron et al Canadian Med Assoc Jnl 2006 Gilron et al Canadian Med Assoc Jnl 2006

MECHANISMS OF ACTION OF TRICYCLIC ANTIDEPRESSANTS

Presynapticneuron

Biogenic amines

(NE + 5HT)

Postsynapticneuron

SYSTEMATIC REVIEW OF SYSTEMATIC REVIEW OF ANTIDEPRESSANTSANTIDEPRESSANTS

IN NEUROPATHIC PAININ NEUROPATHIC PAIN

N N T -- at least 50% pain reliefN N T -- at least 50% pain relief

Diabetic NeuropathyDiabetic Neuropathy 3.03.0

Postherpetic NeuralgiaPostherpetic Neuralgia 2.32.3

H.J. McQuay, M. Tramer et al.H.J. McQuay, M. Tramer et al.

Pain 1996; 68: 217 - 227Pain 1996; 68: 217 - 227

H.J. McQuay, M. Tramer et al.H.J. McQuay, M. Tramer et al.

Pain 1996; 68: 217 - 227Pain 1996; 68: 217 - 227

COMMON SIDE EFFECTS ASSOCIATED COMMON SIDE EFFECTS ASSOCIATED WITH TRICYCLIC ANTIDEPRESSANTSWITH TRICYCLIC ANTIDEPRESSANTS

0/+, minimal; +, mild; ++, moderate; +++, moderately severe.

Goodman and Gilman's

The Pharmacological Basis of Therapeutics, 9th edition.

0/+, minimal; +, mild; ++, moderate; +++, moderately severe.

Goodman and Gilman's

The Pharmacological Basis of Therapeutics, 9th edition.

Sedation Sedation

Anti-cholinergic

effects

Anti-cholinergic

effects HypotensionHypotensionCardiac effects

Cardiac effects SeizuresSeizures

Weight gain

Weight gain

Amitriptyline

Amitriptyline

Clomipramine Clomipramine

Desipramine

Desipramine

Nortriptyline

Nortriptyline

+++ +++

0/+ 0/+

+ +

++ ++

+++ +++

+ +

+ +

+++ +++

+++ +++

+ +

+ +

++ ++

+++ +++

++ ++

++ ++

+++ +++

++ ++

+ +

+ +

+++ +++

++ ++

+ +

+ +

+ +

SNRI’S IN THE MANAGEMENT SNRI’S IN THE MANAGEMENT OF PERIPHERAL OF PERIPHERAL

NEUROPATHIC PAINNEUROPATHIC PAINNNTNNT

Venlafaxine 4.0 Venlafaxine 4.0

Duloxetine 4.1Duloxetine 4.1

GABAPENTIN CHEMICAL STRUCTURE

Amino acidAmino acid Structurally related to the neurotransmitter GABA: Structurally related to the neurotransmitter GABA:

however, gabapentin is not a GABA-mimetichowever, gabapentin is not a GABA-mimetic Crosses blood-brain barrierCrosses blood-brain barrier

CH2NH2CH2NH2

CH2CO2HCH2CO2H

Kupferberg, 1992. Toor, 1993. Kupferberg, 1992. Toor, 1993.

Pregabalin Modulates Hyperexcited NeuronsPregabalin Modulates Hyperexcited Neurons

*Does not affect Ca2+ influx in normal neurons

Gabapentin for the symptomatic treatment of painful neuropathy in patients with

diabetes mellitus

Backonja M et al Backonja M et al

JAMA 1998; 280:1831-1836JAMA 1998; 280:1831-1836

CHANGE IN MEAN PAIN SCORES

Pregabalin in DPN: Reduction in PainPregabalin in DPN: Reduction in Pain

0

2

4

6

8

10

0 1 2 3 4 5 6

Week

Me

an

pa

in s

co

re

Placebo (n=97)

Pregabalin 75 mg/day (n=77)

Pregabalin 300 mg/day (n=81)

Pregabalin 600 mg/day (n=82)

*P<0.001 vs. placebo

*

Lesser et al. Neurology. 2004;63(11):2104-10

**

** * * ** * * *

EP

22-- Modulators: Differences Modulators: Differences

Between Pregabalin and GabapentinBetween Pregabalin and GabapentinPregabalinPregabalin GabapentinGabapentin

22-- binding affinitybinding affinity 19 nM19 nM 140 nM140 nM

Anticonvulsant activity (rat Anticonvulsant activity (rat electroshock)electroshock)

1.3 mg/kg (ED1.3 mg/kg (ED5050)) 9.1 mg/kg (ED9.1 mg/kg (ED

5050))

Neuropathic pain activity Neuropathic pain activity (rat diabetes)(rat diabetes) 3 mg/kg (MED)3 mg/kg (MED) 10 mg/kg (MED)10 mg/kg (MED)

AbsorptionAbsorption Non-saturable across Non-saturable across dose rangedose range SaturableSaturable

Oral bioavailabilityOral bioavailability ≥ ≥ 90%90% ≤ ≤ 50%50%

Daily dosingDaily dosing BID/TIDBID/TID TIDTID

Data on file Pfizer Inc

LIDOCAINE PATCH: DOUBLE-BLIND CONTROLLED STUDY OF A NEW TREATMENT METHOD FOR POST-

HERPETIC NEURALGIA

Rowbotham, M., Davies, P. et al.Rowbotham, M., Davies, P. et al.

Pain 1996; 65: 39-44Pain 1996; 65: 39-44

Rowbotham, M., Davies, P. et al.Rowbotham, M., Davies, P. et al.

Pain 1996; 65: 39-44Pain 1996; 65: 39-44

Lidocaine containing patches significantly Lidocaine containing patches significantly reduced pain intensity at all time points 30 min reduced pain intensity at all time points 30 min to 12 h compared to no-treatment, and at all to 12 h compared to no-treatment, and at all time points 4 - 12 h compared to vehicle time points 4 - 12 h compared to vehicle patches. This study demonstrates that topical patches. This study demonstrates that topical 5% lidocaine in patch form is easy to use and 5% lidocaine in patch form is easy to use and relieves post-herpetic neuralgia.relieves post-herpetic neuralgia.

TRAMADOLTRAMADOL

• Novel analgesic – available in US since 1995

• Weak mu agonist – low risk of tolerance and

dependence

• Inhibitor of noradrenaline and serotonin reuptake

DOUBLE-BLIND RANDOMIZED TRIAL OF DOUBLE-BLIND RANDOMIZED TRIAL OF TRAMADOL FOR THE TREATMENT OF THE TRAMADOL FOR THE TREATMENT OF THE

PAIN OF DIABETIC NEUROPATHYPAIN OF DIABETIC NEUROPATHY

Y. Harati, C. Gooch et al.Y. Harati, C. Gooch et al.

Neurology 1998; 50: 1842 - 1846Neurology 1998; 50: 1842 - 1846

“Tramadol, at an average dosage of 210 mg/day, was significantly (p<.001) more

effective than placebo for treating the pain of diabetic neuropathy”

DOUBLE-BLIND PLACEBO CONTROLLED STUDIESDOUBLE-BLIND PLACEBO CONTROLLED STUDIES OF OPIOIDS IN CHRONIC NON-CANCER PAIN OF OPIOIDS IN CHRONIC NON-CANCER PAIN

1. Maier et al Pain 2002; 2. Raja et al Neurol 2002; 3. Moulin et al Lancet 1996; 4. Huse et al Pain 2001; 5. Caldwell et al JPSM 2002; 6. Watson et al Pain 2003; 7. Watson et al Neurol 1998; 8. Gimbel et al Neurol 2003; 9. Roth et al Arch Intern Med 2000; 10. Caldwell et al Rheum 1999; 11. Arkinstall et al Pain 1995; 12. Peloso et al Rheum 2000; 13.Harati et al Neurology 1998.

1. Maier et al Pain 2002; 2. Raja et al Neurol 2002; 3. Moulin et al Lancet 1996; 4. Huse et al Pain 2001; 5. Caldwell et al JPSM 2002; 6. Watson et al Pain 2003; 7. Watson et al Neurol 1998; 8. Gimbel et al Neurol 2003; 9. Roth et al Arch Intern Med 2000; 10. Caldwell et al Rheum 1999; 11. Arkinstall et al Pain 1995; 12. Peloso et al Rheum 2000; 13.Harati et al Neurology 1998.

Diabet

ic N

euro

path

y (n

=36)

Diabet

ic N

euro

path

y (n

=36)

Post-h

erpet

ic n

eura

lgia

(n=3

8)

Post-h

erpet

ic n

eura

lgia

(n=3

8)

Arthrit

is a

nd Bac

k Pai

n (n=3

0)

Arthrit

is a

nd Bac

k Pai

n (n=3

0)

Ost

eoar

thrit

is (n

=66)

Ost

eoar

thrit

is (n

=66)

Posther

petic

Neu

ralg

ia (n

=76)

Posther

petic

Neu

ralg

ia (n

=76)

Ost

eoar

thrit

is (n

=70)

Ost

eoar

thrit

is (n

=70)

Diabet

ic N

euro

path

y (n

=159

)

Diabet

ic N

euro

path

y (n

=159

)

Ost

eoar

thrit

is (n

=133

)

Ost

eoar

thrit

is (n

=133

)

Musc

ulosk

elet

al P

ain (n

=42)

Musc

ulosk

elet

al P

ain (n

=42)

Phanto

m L

imb

Pain (n

=12)

Phanto

m L

imb

Pain (n

=12)

% R

edu

cti

on

in P

ain

Inte

ns

ity

(

rela

tive

to

pla

ce

bo

)

Mix

ed P

ain S

yndro

mes

(n=4

9)

Mix

ed P

ain S

yndro

mes

(n=4

9)

Diabet

ic N

euro

path

y (1

31)

(6 weeks)(1-4 weeks)(4-6 weeks)(1-9 weeks)

Ost

eoar

thrit

is (n

=295

)

Ost

eoar

thrit

is (n

=295

)

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

METHADONEMETHADONE

• Synthetic opioid – two drugs in one

• L-methadone - opioid analgesic

• D-methadone - NMDA antagonist activity

• oral bioavailability 80%

• elimination half-life about 24 hrs

• no known active metabolites

• low cost

Methadone in the Management of Neuropathic Pain

Moulin et al, Can J Neurol Sci 2005; 32: 340-343

Outcome

1926

5 "Success" group

"Failed" Group

"Diminished" Group

Endocannabinoid System Endocannabinoid System OverviewOverview

IV. Endocannabinoid System

Cannabinoid receptors

G protein-coupled receptors

CB1

CNS and PNS

CB2

Immune system

Endocannabinoids

Anandamide2-arachidonoyl-glycerol (2-AG)2-arachidonoyl-glyceryl ether

Formulation: THC:CBD 1:1Formulation: THC:CBD 1:1

Extracts of 2 Extracts of 2 Cannabis sativa LCannabis sativa L strains strains Equal amounts of Equal amounts of

TetranabinexTetranabinex®®: high-THC strain : high-THC strain 27 mg/mL 27 mg/mL ΔΔ-9 THC-9 THC

NabidiolexNabidiolex®®: high-CBD strain : high-CBD strain 25 mg/mL CBD25 mg/mL CBD

Buccal spray Buccal spray Ethanol/propylene glycol vehicleEthanol/propylene glycol vehicle 2.7 mg THC and 2.5 mg CBD per 2.7 mg THC and 2.5 mg CBD per spray spray

Therapeutic Therapeutic dose dose High inter-patient variabilityHigh inter-patient variability Administered on self-titration regimenAdministered on self-titration regimen

V. Cannabis-based Medicinal Extracts

Clinical Review: Rog et al Clinical Review: Rog et al (Neurology (Neurology 20052005))

Scale0 = No pain10 = Worst possible pain *Active vs placebo

Pain scores at end of randomized treatment phase

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

Baseline On treatment

Me

an

NR

S-1

1 p

ain

sco

re

THC:CBD 1:1 Placebo

N =34

N =32

N =32

N =32

p =0.005*

V. Cannabis-based Medicinal Extracts

TCA or SNRI

PREGABALIN or GABAPENTIN

TRAMADOL** OPIOID ANALGESIC

TOPICAL LIDOCAINE 5% GEL or PATCH

MISCELLANEOUS AGENTS eg CANNABINOIDS* Add agent from opposite column for complementary treatment** Only available in Canada as a fixed-dose combination with acetaminophen***Probable drug of first choice for focal neuropathy such as postherpetic neuralgia. Lidocaine patch not available in Canada

OR*

Add additional agents sequentially if partial but incomplete pain

relief

STEPWISE PHARMACOLOGIC STEPWISE PHARMACOLOGIC

MANAGEMENT OF NEUROPATHIC PAINMANAGEMENT OF NEUROPATHIC PAIN

STEPWISE PHARMACOLOGIC STEPWISE PHARMACOLOGIC

MANAGEMENT OF NEUROPATHIC PAINMANAGEMENT OF NEUROPATHIC PAIN

***

INTERVENTIONAL TECHNIQUES INTERVENTIONAL TECHNIQUES

Lidocaine/steroid injections into sites of Lidocaine/steroid injections into sites of nerve entrapmentnerve entrapment

IV lidocaine infusionsIV lidocaine infusionsSympathetic blockadeSympathetic blockadeEpidural steroid injectionsEpidural steroid injectionsSpinal cord stimulationSpinal cord stimulation

MANAGEMENT OF MANAGEMENT OF NEUROPATHIC PAIN NEUROPATHIC PAIN

THE FUTURETHE FUTUREPrevention – zoster vaccine to prevent Prevention – zoster vaccine to prevent

zoster infection and PHN( NEJM 2005)zoster infection and PHN( NEJM 2005)

Novel Agents – microglial antagonists?-Novel Agents – microglial antagonists?-

role of brain-derived neurotrophic factorrole of brain-derived neurotrophic factor

(BDNF) in sensitization of the dorsal (BDNF) in sensitization of the dorsal horn (Nature 2005)horn (Nature 2005)

Anterolateral pathway (to brain)

Neuroma

Bulbospinal DescendingSystems (from brain)

Interneuron

P2X4TNFIL-1Neurotorphins microglia

c

cb

a

a

b

↑Nav↓Kv

AA c

Sympatheticsprouting

DRG

↓KCC2

Nerve injury-induced changes in the periphery, dorsal root ganglia, and spinal cord contribute to neuropathic pain syndromes.

-

+-

+

PHARMACOLOGIC TREATMENT PHARMACOLOGIC TREATMENT FOR NEUROPATHIC PAINFOR NEUROPATHIC PAIN

FUTURE CONSIDERATIONSFUTURE CONSIDERATIONS1)1) Do these agents provide sustained Do these agents provide sustained

pain relief in the longterm?pain relief in the longterm?

2)2) Do these agents improve overall Do these agents improve overall quality of life in the longterm?quality of life in the longterm?

3)3) What are the longterm effects of What are the longterm effects of opioids on the neuroendocrine and opioids on the neuroendocrine and immunological systems?immunological systems?