NEUROLOGICAL COMPLICATIONS OF DIABETES AND TREATMENT OF NEUROPATHIC PAIN Dwight Moulin MD Depts of...
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Transcript of NEUROLOGICAL COMPLICATIONS OF DIABETES AND TREATMENT OF NEUROPATHIC PAIN Dwight Moulin MD Depts of...
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?