1. Dwight Moulin MD Depts of CNS and Oncology UWO
NEUROLOGICAL COMPLICATIONS OF DIABETES AND TREATMENT OF NEUROPATHIC PAIN
Dwight Moulin MD
Depts of CNS and Oncology
UWO

2. Disclosure Statement
I have had a professional association with the following organizations
Pfizer Canada
Purdue Pharma
Janssen-Ortho
Bayer

3. Neurological Complications of Diabetes Mellitus
CNS metabolic
- cerebrovascular disease
PNS focal
- generalized

4. Diabetic Neuropathies
Focal abrupt in onset
- severe pain
- resolve spontaneously in
months to 1 to 2 years
Generalized - insidious in onset
- initially painless
- progressive

5. Focal Diabetic Neuropathies
Ocular palsies – 3rd/ 6th nerves
Brachial plexopathy
Thoracic (truncal) radiculopathy
Lumbosacral plexopathy
Entrapment neuropathies

6. Generalized Diabetic Neuropathy
Distal sensori-motor neuropathy
Autonomic neuropathy

9. Knee Reflex

10. Dermatomes – Lower Extremities

11. PAINFUL DIABETIC NEUROPATHY
Diabetes Mellitus
50%
Diabetic Neuropathy
10%
Painful Diabetic Neuropathy

12. CLINICAL FEATURES OF NEUROPATHIC PAIN
Dysesthetic burning pain
Paroxysmal lancinating pain
Touch-evoked pain (allodynia)

13. ADVANCES IN NEUROPATHIC PAIN FIRST-LINE MEDICATIONS (Class I Evidence)
Gabapentin/Pregabalin
TCAs/SNRIs
5% Lidocaine Patch
Tramadol
Opioid Analgesics
Dworkin et al Archives of Neurology 2003
Gilron et al Canadian Med Assoc Jnl 2006

14. MECHANISMS OF ACTION OF TRICYCLIC ANTIDEPRESSANTS
Presynaptic
neuron
Biogenic amines
(NE + 5HT)
Postsynaptic

15. SYSTEMATIC REVIEW OF ANTIDEPRESSANTS IN NEUROPATHIC PAIN
N N T -- at least 50% pain relief
Diabetic Neuropathy 3.0
Postherpetic Neuralgia 2.3
H.J. McQuay, M. Tramer et al.
Pain 1996; 68:

16. COMMON SIDE EFFECTS ASSOCIATED WITH TRICYCLIC ANTIDEPRESSANTS
Sedation
Anti-cholinergic effects
Hypotension
Cardiac effects
Seizures
Weight gain
Amitriptyline
Clomipramine
Desipramine
Nortriptyline
+++
0/+ + ++
0/+, minimal; +, mild; ++, moderate; +++, moderately severe.
Goodman and Gilman's
The Pharmacological Basis of Therapeutics, 9th edition.

17. SNRI’S IN THE MANAGEMENT OF PERIPHERAL NEUROPATHIC PAIN NNT
Venlafaxine
Duloxetine

18. GABAPENTIN CHEMICAL STRUCTURE
CH2NH2
CH2CO2H
Amino acid
Structurally related to the neurotransmitter GABA: however, gabapentin is not a GABA-mimetic
Crosses blood-brain barrier
Kupferberg, 1992.
Toor, 1993.

19. Pregabalin Modulates Hyperexcited Neurons
The key points on this slide are as follows:
The mechanism of action of pregabalin is distinct from the several known mechanisms of action of other antiepileptic and analgesic drugs.
Pregabalin modulates hyperexcited neurons via the following mechanism:
Pregabalin binds to presynaptic neurons at the alpha2-delta (a2-d) subunit of voltage-gated calcium channels
Drug binding reduces calcium influx into presynaptic terminals
Decreased calcium influx reduces excessive release of excitatory neurotransmitters (eg, glutamate, substance P, noradrenaline)
Preclinical animal studies indicate that this mechanism of action is responsible for the anticonvulsant, analgesic, and anxiolytic activity of pregabalin.
These findings are derived from work in preclinical experimental models. The clinical significance in humans is not known.
Reference
Data on file, Pfizer Inc, New York, NY, USA
(See previous slides on the effects of pregabalin on calcium influx and neurotransmitter release for additional references)
Additional key words: mechanism of action, MOA, pharmacology, norepinephrine, calcium ion
*Does not affect Ca2+ influx in normal neurons

20. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus
Backonja M et al
JAMA 1998; 280:

21. CHANGE IN MEAN PAIN SCORES
DN study

22. Pregabalin in DPN: Reduction in Pain
*P<0.001 vs. placebo * * * * * * * * * * * *
This slide presents data from a 5-week, randomized, double-blind, placebo-controlled study of LYRICA (pregabalin) in the treatment of painful diabetic peripheral neuropathy (DPN) (study 029). Patients were randomized to, and treated with, LYRICA 75 mg/day (n=77), 300 mg/day (n=81) and 600 mg/day (n=82) or placebo (n=97), taken in a TID (three times daily) dosing schedule. Patients in the 75 and 300 mg/day groups received their full randomized dose from the start of the study. The patient numbers shown on the slide refer to the number of patients included in the primary intention to treat (ITT), last observation carried forward (LOCF) analysis at end point. Changes over time are based on observed case analysis (OC). The primary efficacy variable was, for all pain studies, the mean end point pain score in each LYRICA group compared with placebo, based on pain scores from the last 7 days’ diary entries while patients were on treatment. The mean weekly scores were also compared.
The key talking points for this slide are as follows:
Patients had moderate to severe pain at baseline (mean pain score for all groups ranged from ).
LYRICA 300 and 600 mg/day were significantly more effective in improving pain than placebo as early as week 1, and for the duration of the 5-week study.
LYRICA 75 mg/day was no more effective than placebo and is not within the therapeutic dose range. The therapeutic dose range is mg/day.
Reference
Lesser et al. Neurology. 2004;63(11):
Additional key words: diabetes, diabetic, rapid EP
Lesser et al. Neurology. 2004;63(11):

23. 2- Modulators: Differences Between Pregabalin and Gabapentin
2- binding affinity
19 nM
140 nM
Anticonvulsant activity (rat electroshock)
1.3 mg/kg (ED50)
9.1 mg/kg (ED50)
Neuropathic pain activity (rat diabetes)
3 mg/kg (MED)
10 mg/kg (MED)
Absorption
Non-saturable across dose range
Saturable
Oral bioavailability
≥ 90%
≤ 50%
Daily dosing
BID/TID
TID
This slide summarizes the key pharmacodynamic differences in animal models pharmacokinetic differences in humans between pregabalin and gabapentin, based on pre-clinical pharmacology. Pregabalin and gabapentin both bind to the alpha2-delta (a2-d) subunit.
Key points on this slide are as follows:
Pregabalin is a more potent drug than gabapentin, as shown by the ED50 concentrations required to achieve an anticonvulsant effect in the mouse maximal electroshock model of tonic extensor seizures and in models of neuropathic pain behavior. This is true also in other animal models where both compounds are active. (MED denotes the minimal dose of drug where a significant effect was seen.)
Pregabalin binds to an auxiliary subunit (2- protein) of voltage-gated calcium channels in the central nervous system, potently displacing [3H]-gabapentin.
Pregabalin oral absorption is non-saturable and linear across and above the recommended dose range. By contrast, the absorption of gabapentin is saturable, and oral absorption of gabapentin is neither linear (at higher doses) nor very predictable between individuals.
Pregabalin and gabapentin appear to share one common pathway for absorption, likely Na-independent system L, which is saturable. However pregabalin, unlike gabapentin, is also absorbed by a sodium-dependent pathway in vitro, which is not saturable.
Pregabalin is at least 90% bioavailable irrespective of dose. This is not the case for gabapentin for the reasons described above.
The pharmacokinetic and pharmacodynamic profiles enable pregabalin to be taken in a twice daily or three times dosing regimen, whereas gabapentin should be taken three times daily.
Reference
Data on file, Pfizer Inc, New York, NY, USA
Data on file Pfizer Inc

24. LIDOCAINE PATCH: DOUBLE-BLIND CONTROLLED STUDY OF A NEW TREATMENT METHOD FOR POST-HERPETIC NEURALGIA
Lidocaine containing patches significantly reduced pain intensity at all time points 30 min to 12 h compared to no-treatment, and at all time points h compared to vehicle patches. This study demonstrates that topical 5% lidocaine in patch form is easy to use and relieves post-herpetic neuralgia.
Rowbotham, M., Davies, P. et al.
Pain 1996; 65: 39-44

25. TRAMADOL Novel analgesic – available in US since 1995
Weak mu agonist – low risk of tolerance and
dependence
Inhibitor of noradrenaline and serotonin reuptake

26. Y. Harati, C. Gooch et al. Neurology 1998; 50: 1842 - 1846
DOUBLE-BLIND RANDOMIZED TRIAL OF TRAMADOL FOR THE TREATMENT OF THE PAIN OF DIABETIC NEUROPATHY
“Tramadol, at an average dosage of 210 mg/day, was significantly (p<.001) more effective than placebo for treating the pain of diabetic neuropathy”
Y. Harati, C. Gooch et al.
Neurology 1998; 50:

27. Diabetic Neuropathy (131) % Reduction in Pain Intensity
DOUBLE-BLIND PLACEBO CONTROLLED STUDIES OF OPIOIDS IN CHRONIC NON-CANCER PAIN
Diabetic Neuropathy (n=36)
Post-herpetic neuralgia (n=38)
Arthritis and Back Pain (n=30)
Diabetic Neuropathy (n=159)
Osteoarthritis (n=66)
Mixed Pain Syndromes (n=49)
Osteoarthritis (n=133)
Postherpetic Neuralgia (n=76)
Osteoarthritis (n=70)
Musculoskeletal Pain (n=42)
Phantom Limb Pain (n=12)
Diabetic Neuropathy (131)
Osteoarthritis (n=295)
% Reduction in Pain Intensity
(relative to placebo)
Tramadol, has been added to this slide
(1-9 weeks)
(4-6 weeks)
(1-4 weeks)
(6 weeks)
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.

28. I. Gilron et al. NEJM 2005;352:

29. METHADONE 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

30. Methadone in the Management of Neuropathic Pain
Moulin et al, Can J Neurol Sci 2005; 32:

31. Endocannabinoid System Overview
IV. Endocannabinoid System
Endocannabinoid System Overview
Cannabinoid receptors
G protein-coupled receptors
CB1
CNS and PNS
CB2
Immune system
The endocannabinoid system includes cannabinoid receptors, a family of G protein-coupled receptors, and the endogenous cannabinoids identified.1,2
The CB1 receptor, the only cannabinoid receptor identified in the brain, is widely distributed in the CNS and PNS.1 Its CNS distribution provides a basis for the known effects of cannabis: inhibition of memory, cognitive function and motor activity, and effects on appetite, body temperature, pain and sensory perception and mood/reward.3 Its PNS distribution in sensory and autonomic interneurons of dorsal root ganglia explain THC effects on spinal nociception.
The CB2 receptor is expressed in peripheral tissues, primarily in the immune system, and appears to be involved in immune regulatory functions affected by THC.3
The endocannabinoids, natural ligands of the cannabinoid receptors, are a family of arachidonic acid derivatives that function as lipid messengers, diffusing through the synaptic space.1 The endocannabinoids include anandamide, 2-arachidonoyl-glycerol (2-AG), and 2-arachidonoyl-glyceryl ether. Anandamide is the most studied endocannabinoid.
References
Iversen L. Cannabis and the brain. Brain 2003;126:
Piomelli et al. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003;4:
Di Marzo V et al. Endocannabinoids Part I: Molecular basis of endocannabinoid formation, action and inactivation and development of selective inhibitors. Emerg Ther Targets 2001;5:
Endocannabinoids
Anandamide
2-arachidonoyl-glycerol (2-AG)
2-arachidonoyl-glyceryl ether

32. Formulation: THC:CBD 1:1
V. Cannabis-based Medicinal Extracts
Formulation: THC:CBD 1:1
Extracts of 2 Cannabis sativa L strains
Equal amounts of
Tetranabinex®: high-THC strain
27 mg/mL Δ-9 THC
Nabidiolex®: high-CBD strain
25 mg/mL CBD
Buccal spray
Ethanol/propylene glycol vehicle
2.7 mg THC and 2.5 mg CBD per spray
Therapeutic dose
High inter-patient variability
Administered on self-titration regimen
This formulation, THC:CBD 1:1, contains equal amounts of Tetranabinex® and Nabidiolex® extracts of Cannabis sativa L. in an oromucosal spray.
Tetranabinex® (THC Botanical Drug Substance (BDS)) contains 27 mg/mL Δ-9 THC, which makes up at least 60% of the extract. Other cannabinoids make up 10% or less of the Δ-9 THC content, and the non-cannabinoid fraction (terpenes, flavonoids and other plant material) accounts for 30 to 40% of the BDS.
Nabidiolex® (CBD BDS) contains 25 mg/mL CBD, which comprises at least 55% of the extract. Other cannabinoids make up 18% or less of the CBD content and the non-cannabinoid fraction comprises 30 to 40% of the BDS.
An ethanol and propylene glycol vehicle is used for this buccal spray, and each 100-μL spray delivers 2.7 mg THC and 2.5 mg CBD.
THC:CBD 1:1 is administered on a self-titration regimen. The self-titration regimen has been selected because the therapeutic dose shows high inter-patient variability.1
Reference
1. Sativex® Product Monograph. Bayer Inc

33. Clinical Review: Rog et al (Neurology 2005)
V. Cannabis-based Medicinal Extracts
Clinical Review: Rog et al (Neurology 2005)
Pain scores at end of randomized treatment phase
7.00
6.00
p =0.005*
N =34
N =32
5.00
N =32
4.00
Mean NRS-11 pain score
N =32
3.00
2.00
Slide illustrates change in pain scores from baseline to end of 4-week treatment period.
A statistically significant mean reduction favouring THC:CBD 1:1 was seen for the primary outcome, the change in pain score on the NRS-11 (P=0.005). A statistically significant mean treatment difference of –1.25, favouring active treatment, was seen between THC:CBD 1:1 and placebo (P=0.005). In addition, a statistically significant difference (P=0.044) was seen for the exploratory outcome, scoring pain using the NPS, with a total mean treatment difference of –6.58 (95% CI – 2.97, – 0.19). NPS data are not shown.
The data analysis compared the differences in scores (taking into account baseline values) seen with THC:CBD 1:1 and placebo, rather than the final versus baseline scores for THC:CBD 1:1 and placebo.
Reference
Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized controlled trial of cannabis based medicine in central pain due to multiple sclerosis. Accepted for publication in Neurology 2005.
1.00
0.00
Baseline
On treatment
Scale
0 = No pain
10 = Worst possible pain
THC:CBD 1:1
Placebo
*Active vs placebo

34. STEPWISE PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN
TCA or SNRI
PREGABALIN or GABAPENTIN
OR*
Add additional agents sequentially if partial but incomplete pain relief
TRAMADOL**
OPIOID ANALGESIC
TOPICAL LIDOCAINE 5% GEL or PATCH
***
This slide has been reformatted.
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

35. INTERVENTIONAL TECHNIQUES
Lidocaine/steroid injections into sites of nerve entrapment
IV lidocaine infusions
Sympathetic blockade
Epidural steroid injections
Spinal cord stimulation

36. MANAGEMENT OF NEUROPATHIC PAIN THE FUTURE
Prevention – zoster vaccine to prevent zoster infection and PHN( NEJM 2005)
Novel Agents – microglial antagonists?-
role of brain-derived neurotrophic factor
(BDNF) in sensitization of the dorsal horn (Nature 2005)

37. Bulbospinal Descending
Nerve injury-induced changes in the periphery, dorsal root ganglia, and spinal cord contribute to neuropathic pain syndromes. b a a
Neuroma c
Bulbospinal Descending
Systems (from brain)
↓Kv
↑Nav - + - b +
Interneuron
TNF
IL-1
Neurotorphins
P2X4 A
microglia A c
↓KCC2
Anterolateral
pathway (to brain)
Sympathetic
sprouting
DRG

38. PHARMACOLOGIC TREATMENT FOR NEUROPATHIC PAIN FUTURE CONSIDERATIONS
Do these agents provide sustained pain relief in the longterm?
Do these agents improve overall quality of life in the longterm?
What are the longterm effects of opioids on the neuroendocrine and immunological systems?