prof. solomon tesfaye mb chb, md, frcp · 2019-05-18 · preventing and managing diabetic...
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Preventing and Managing Diabetic Neuropathy
• Prof. Solomon Tesfaye MB ChB, MD, FRCP• Academic Director of Diabetes & EndocrinologySheffield Teaching Hospitals & the University of Sheffield
Visiting Professor at Xiangya Hospital Central Southern University• Visiting professor at Shanghai Jiao Tong University
DPN, diabetic peripheral neuropathy
Preventing and Managing Diabetic Neuropathy
Late diagnosis of DPN1
Peripheral biomarkers of DPN and painful DPN2
Central biomarkers of DPN and painful DPN3
Management of DPN4
Conclusions5
DPN, diabetic peripheral neuropathy
Late diagnosis of DPN1
Preventing and Managing Diabetic Neuropathy
DPN is common affecting 1 in 2 people with DM
Diabetic Polyneuropathy (DPN)
Pain in 25%
Many DPN clinical phenotypes
DPN, diabetic peripheral neuropathy; CVA, Cerebrovascular accident; IHD, Ischaemic heart disease; PVD, Peripheral vascular disease.Tesfaye et al. Diabetes Metab Res Rev 2011; 27: 629–638. Tesfaye et al. J Diabetes Investig. 2011; 24;2(1):33-42.
AnxietyDepression
AngerFear
Loss of confidence
Psychological
Job lossMarital
disharmonyIsolation
Loss of social status
Social
Painful DPN Under-diagnosed
Visual lossObesity
Nephropathy Ulcers
VasculopathyPVD/IHD/CVA
UnsteadinessandFalls
Autonomic neuropathy
Patient verbal descriptors of pain, questions and answers
Nervous system lesion or abnormality
Sensory abnormalities (skin and joints)
1.Gilron I et al. CMAJ 2006;175:265-75. 2. Haanpää ML et al. Am J Med 2009;122(10 Suppl):S13-21.3. Baron R, Tölle TR. Curr Opin Support Palliat Care 2008;2:1-8.
The 3L Approach to dragnosis
1.Baron R, Tölle TR. Curr Opin Support Palliat Care 2008;2:1-8.2.Gilron I et al. CMAJ 2006;175:265-75.
1.Gilron I et al. CMAJ 2006;175:265-75.2.Baron R, Tölle TR. Curr Opin Support Palliat Care 2008;2:1-8.3.Haanpää ML et al. Am J Med 2009;122(10 Suppl):S13-21.
Probablenociceptive pain
Can you detect sensoryabnormalities using
simple bedside tests?1-3
Are verbal descriptorssuggestive of neuropathic pain?1
Neuropathic pain syndromelikely: initiate treatment3
Can you identify theresponsible nervous system
lesion/dysfunction?3
Consider specialist referral, andif neuropathic pain is still
suspected consider treatment in the interim period3
Making a differential diagnosis
The neuropathic process starts early in Diabetes
Intraepidermal nerve fibre density (IENFD)Punch biopsy, 3 mm Ø, distal lateral calf
Small fibre neuropathy
Healthy subject
IENFD in recent-onset T2D (N-DM) vs painful (DSPN+p)and painless (DSPN-p) diabetic polyneuropathy
DSPN, diabetic sensory peripheral neuropathy; N-DM: newly diagnosed diabetes mellitus; -p, painless; +p, painful; T2D, type 2 diabetesBönhof GJ, et al. Diabetologia. 2017;60:2495–2503. 9
Diabetic Neuropathy: A Position Statement by the American Diabetes Association
Pop-Busui R, et al. Diabetes Care 2017;40:136-154
Recommendations• T2DM - assess for DPN from diagnosis• T1DM - assess for DPN 5 years after diagnosis • Annually thereafter• Consider screening patients with pre-diabetes and symptoms of DPN• Assessment should include:
• Comprehensive history• Temperature/pinprick sensation (to assess small-fiber function)• Vibration sensation with 128-Hz tuning fork (to assess large fiber function)
• 10-g monofilament testing to assess risk for ulceration/ amputation• When the clinical features are atypical, the diagnosis is unclear, or a the patient
should either be referred to a neurologist or undergo EMG
Unfortunately this is not happening!
Binns-Hall O, et al. Diabet Med. 2018 Apr 2. doi: 10.1111/dme.13630. [Epub ahead of print]
11
Combined foot/eye/renal screeninguncovers new diagnosis of DPN
and painful-DPN: A “one stop shop”1
DPN, diabetic peripheral neuropathy1. Binns‐Hall O, et al. Diabet Med. 2018 Apr 2. doi: 10.1111/dme.13630. [Epub ahead of print]2. Bouhassira D, et al. Pain. 2005;114(1-2):29-36.
SUDOSCANDPN-Check
DN4 Questionnaire2
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ResultsDemographic parameters
n 236Gender (%, male) 61.4Mean age (years) 63.5Type 2 diabetes (%) 97.8Mean Hba1c (mmol/mol) 61.2Monofilament positive DPN (%) 14.4TCSS ≥5 = DPN (%) 30.7Sudoscan (foot ESC) >60uS = DPN (%) 38.2
DPN-check cut off for DPN (age/height adjusted)(%) 51.5
Documented evidence of foot screening in past yr (%) 19
New diagnosis of painful DPN (%) [mean 24hr NRS 5.3] 25
DPN, diabetic peripheral neuropathy; ESC, electrochemical skin conductance; Hba1c, glycosylated haemoglobin; NRS, numerical rating scale;TCSS, Toronto Clinical Scoring SystemBinns-Hall O, et al. Diabet Med. 2018 Apr 2. doi: 10.1111/dme.13630. [Epub ahead of print] 13
DPN, diabetic peripheral neuropathy
Peripheral biomarkers of DPN and painful DPN2
Preventing and Managing Diabetic Neuropathy
Narrowing of individual capillaries might not prevent blood from passing through the endoneurial capillary bed, but the resulting increase in velocity of blood through endoneurial functional shunts or epineurial arteriovenous shunts prevents efficient oxygen extraction, causing hypoxia.1
Vascular cause of neuronal damage in DPN
DPN, diabetic peripheral neuropathyGoncalves NP, et al. Nat Rev Neurol. 2017;13(3):135-147 15
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S, et al. Diabetologia. 1993;36:1266—74
Artery
Vein
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension1.57
1.38
1.48
1.36
1.40
1.27
1.21
1.15
Model 1:without CVDand retinopathy
Odds ratios (95% CI)
n=1101 with type 1 DM; FU: 7.3±0.6 yrs
Tesfaye et al. N Engl J Med 2005; 352: 341-50.
0 1 2 3 4
Skin Intra-epidermal (e) and sub-epidermal (f) nerve fibres in healthy volunteers and diabetic subjects with No-DPN, Painful- and Painless-DPN
Shillo P et al. Diabetologia 2017(Abstract)
Healthy volunteers (Control)
No-DPN (NDN)
Painful DPN(P)
Painless DPN(NP)
GAP 43 in epidermal (e) and sub-epidermal (f) nerve fibres in healthy controls and diabetic subjects with No-DPN, Painful- and Painless-DPN
Shillo P et al. Diabetologia 2017(Abstract)
Healthy volunteers
No-DPN
Painful DPN
Painless DPN
HV (Control) Painful DPN (P)
Painless DPN Type 2 DM (NDN)
Shillo P et al. Diabetes Care Under review
Dermal Microvascular Proliferation
Normal TIND
Acute “Insulin Neuritis”
Tesfaye S, et al. Diabetologia. 1996;39:329–35
Studies have not assessed potential confounding factors:• Seasonal sunlight exposure • Daily activity • DPN assessment was not optimal • Pain was not assessed and /or phenotyped appropriately
23
Vitamin D Levels
ANCOVA P= 0.01
- There was a significant negative correlation between HbA1c and serum25(OH)D levels (r = 0.36, P = 0.01).
- Lower 25-hydroxyvitamin D levels correlated with lower cold detectionthresholds (r = 0.39, P = 0.02) and sub-epidermal nerve fibre densities (r = 0.42,P = 0.01).
Genetic variability in painful DPN patients:
pDPN, painful diabetic peripheral neuropathyBlesneac I, et al. Pain. 2018;159(3):469-480.
NaV1.7 is a voltage-gated sodium channel that has been shown to be related to neuropathic pain:
•Expressed in nociceptors and amplifies sub-threshold stimuli•A key determinant of nociceptor excitability•Important in pathological pain states in humans•Homozygous loss of function mutations in NaV1.7 have been shown to cause congenital insensitivity to pain
•Heterozygous gain of function variants associated with pain disorders including inherited erythromelalgia and paroxysmal extreme pain disorder
inherited)
COOHNH2
EC
IC
Nav1.7
26
Rare NaV1.7 variants contribute to the development NeuP in patients with DPN
The relationship between variants of NaV1.7 and neuropathic pain were examined inpatients with DPN
DPN, diabetic peripheral neuropathyBlesneac I, et al. Pain. 2018;159(3):469-480.
NaV1.7
No rare variants in 78 patients with painless DPN
12 rare variants identified in painful DPN group
5/12 had previously been described in the context of other neuropathic pain disorders
7/12 have not previously been linked to neuropathic pain
Rare NaV1.7 variants associated with painful DPNBlesneac L, Themistocleous AC, Fratter C, Conrad LJ, Ramirez JD, Cox J, Tesfaye S, Shillo P, Rice A, Tucker SJ, Bennett D.
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DPN, diabetic peripheral neuropathy
Central biomarkers of DPN and painful DPN3
Preventing and Managing Diabetic Neuropathy
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Hyper-perfusion of the anterior cingulate cortex can be normalised by duloxetine treatment
Anterior cingulate cortex activation plays an important role in the development of central sensitization in response to
peripheral neuropathic pain
CBF, cerebral blood flowWatanabe K, et al. J Nrutol Neurosurg Psychiatry 2018 [Epub ahead of print]
• CBF plots of before and after duloxetine treatment in patients with diabetes and pain
• The patients were classified as responders or non-responders
A. CBF in anterior cingulate cortex. Significant decreases were observed only in the responder groupB. CBF in the nucleus accumbens remained unchanged in both groups
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Complications
Structural and Functional Abnormalities of the Primary Somatosensory Cortex
. Dinesh Selvarajah1⇑, Iain D. Wilkinson2, Fang Fang3, Adithya Sankar2, Jennifer Davies2, Elaine Boland2,Jo
-
Author Affiliations
. 1Department of Human Metabolism, University of Sheffield, Sheffield, U.K.
. 2Academic Unit of Radiology, University of Sheffield, Sheffield, U.K.
. 3Department of Neurophysiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K.
Response to Thermal Pain on fMRI
Neuropathic site Non-neuropathic control site
fMRI activation patterns in response to heat pain applied to the foot
Cluster level Corrected p < 0.05Uncorrected for display purposes
Painful Insensate-62 -6 18
HV-6 -38 58
Painless DN-10 -46 76
Painful Sensate-12 -46 78
Diabetes 2019
HV-10 -38 80
Painful sensate-12 -46 78
Painful Insensate-58 -14 36
Painless DN-12 -44 58
Cluster level Corrected p < 0.05Uncorrected for display purposes
fMRI activation patterns in response to heat pain applied to the THIGH
Diabetes 2019
DPN, diabetic peripheral neuropathy
Preventing and Managing Diabetic Neuropathy
Management of DPN4
Pain Insensitivity
Symptomatic Pathogenic
Risk Reduction
NEUROPATHY
Ward JD et al Lancet 1971 Feb 27;1(7696): 428-30.
Improvement in nerve conduction following treatment in newly diagnosed
diabetics.
Professor JD Ward
IGT, impaired glucose tolerance; DPN, diabetic peripheral neuropathy; IENFD, intraepidermla nerve fibre density; VAS, visual analog score Smith et al., Diabetes Care 2006; 29: 1294-9.
Lifestyle Intervention In IGT With Painful DPNEpidermal “Reinnervation” After 1 Year (n=32)
Correlation Between ImprovementIn Intraepidermal Nerve Fibre Density
(IENFD) And Improvement In Pain
12 Months
IENFD15/mm
Baseline
IENFD8/mmr=0.4
p<0.05
VAS
Chan
ge (m
m)
IENFD Proximal Thigh Change (fibres/mm)
60
40
20
0
-20
-40
-60
-80-4 -2 0 2 4 6 8
Pathogenesis of Diabetic Neuropathy
Hyperglycemia
Free transition metal ionsAutoxidationAGE formationEndogenous scavengersReactive Oxygen Species
Diabetes
Polyolpathwayflux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC ß
AII
ET
NO
PGI2EDHF
VasculardysfunctionNerve and ganglion
blood flowEndoneurial hypoxia
Ischemia/reperfusionA-V shunting
ONOO-
Cameron et al., Diabetologia, 2001; 44:1973 –88
PKCßInhibitor
ARIs
Antioxidantsαα -Lipoic acid
Linoleic acid
GLA
DGLA
AA
GLA
AGEInhibitors
ACE-I., ARB
C-Peptide
MDT: Doctor, Nurse, Physiotherapist,Pain Specialist,
PsychologistPodiatrist+2
Counselling2,3
BehaviouralTherapy1
GlycaemicControl2
LifestyleChange3
Neuromodulation1
ComplementaryTherapies1
Pharmacotherapy1,3
PhysicalTherapy1
AssistiveDevices2
Multimodal Approach To Management
1. Vinik AI, Casellini CM. Diabetes Metab Syndr Obes. 2013;6:57-78. 2. Kaku M, et al. Curr Diab Rep. 2015;15(6):609.
3. Yoo M, et al. J Diabetes Metab. 2013;10.
MDT, multidisciplinary team.
42
Neuropathic Pain Treatment GuidelinesOral Pharmacotherapy
Medication Class
2015 NeuPSIG
Guidelines†
2013NICE (UK)
Guidelines‡
Tricyclic antidepressants First line First line
Calcium channel α2-δ ligand
(gabapentin, gabapentin enacarbil and pregabalin)
First line First line
SNRIs (duloxetine and venlafaxine) First line First line
Tramadol Second line Only if acute rescue therapy
Opioid analgesics Third line Specialists only
†NEUPSIG: Recommendations for the use of opioids might be different in certain cancer populations. Similarly, these recommendations do not apply to acute pain or acute pain exacerbation Not included: Lidocaine and capsaicin patches (second line), and botulinum toxin A (third line) which are recommended for peripheral neuropathic pain only (in the area of pain). ‡ NICE: Carbamazepine for trigeminal neuralgia
Please refer to Summary of Product Characteristics in your country as not all products are approved for the treatment of neuropathic pain. † NeuPSIG: neuropathic Pain Special Interest Group. Finnerup et al. Lancet Neurol 2015; 162–73‡NICE: National Institute for Health and Care Excellence, UK, 2013. guidance.nice.org.uk/cg173. Non-specialist settingsGilron et al. Lancet Neurol 2013; 12: 1084–95
Do not combine TCA & SNRI
NeuPSIG: Strong Recommendations for First-line Use
Treatment Total daily dose and regimen
Gapabentin 1200–3600 mg, in 3 divided doses
Pregabalin 300–600 mg, in 2 divided doses
SNRIs: duloxetine or venlafaxine* 60–120 mg, once a day (duloxetine) 150–225 mg, once a day (venlafaxine ER)
Tricyclic antidepressants 25–150 mg, once a day or in 2 divided doses
Please refer to Summary of Product Characteristics in your country as not all products are approved for the treatment of neuropathic pain. Recommendations based on GRADE classification. NeuPSIG: Special Interest Group of the International Association for the Study of Pain Neuropathic Pain. ER: Extended Release. SNRI: Serotonin-noradrenaline reuptake inhibitor . Finnerup NB et al. Lancet Neurol. 2015;14(2):162-73
*Duloxetine is the most studied, and therefore recommended, of the SNRIs
†Tricyclic antidepressants generally have similar efficacy; tertiary amine tricyclic antidepressants (amitriptyline, imipramine, and clomipramine) are not recommended at doses greater than 75 mg/day in adults aged 65 years and older because of major anticholinergic and sedative side-effects and potential risk of falls; an increased risk of sudden cardiac death has been reported with tricyclic antidepressants at doses greater than 100 mg daily
600mg dose is not available in SA
PDN, painful diabetic neuropathy; TCA, tricyclic antidepressants, SNRI, serotonin-norepinephrine reuptake inhibitorsTesfaye et al. Diabetes Metab Res Rev 2011.
Treatment Algorithm For PDN1
(Consensus)Painful diabetic neuropathy
Add opioid agonist as combination therapy
Consideration of contraindications and comorbidities
α2-δ agonist(pregabalin or gabapentin) TCA SNRI
(duloxetine)
If pain control is inadequate and considering contraindications
TCA or SNRI SNRI or α2-δ agonist(pregabalin or gabapentin)
TCA or α2-δ agonist(pregabalin or gabapentin)
If pain control is still inadequate
600 mg Pregabalin is not a registered dose in SA.
COMBO: Initial Treatment PeriodCOMBO: Intensive Treatment Period (8 weeks)
DLX 120
mg/day: N=74
DLX 60mg/dayPregabalin 300mg/day
N=75
Pregabalin 300mg/day
DLX 60mg/day:
N=95
Pregabalin 600mg/day:
N=99
COMBINATION ARM
HIGH DOSE MONOTHERAPYARM
Non Responders (<30% pain relief)
vs
DLX 60mg/day: N=401
Pregabalin 300mg/day:
N=403
Randomized and Treated: N=804
BPI-MSF, brief pain inventory modified short form Tesfaye et al. Pain 2013; 154:2616-25.
COMBO: Combination vs Monotherapy Primary Outcome Parameter: BPI-MSF
Brief Pain Inventory Modified Short Form 24-hour Average Pain Item Score over Time ‒
Intensive Treatment
-3
-2
-1
0
1
0 4 8Intensive Treatment Period (weeks)
p=0.098
p=0.370
LS M
ean
(95%
CI)
BPI
Ave
rage
Pai
n Sc
ore
Combination Monotherapy
Treatment of Painful DPN Beyond Guidelines:Many Questions: Few Answers?
• Which is the best 1st line drug? • Which combination of 1st line drugs is the best?o : RCT funded by the NIHR
$5,000,000 (Tesfaye, CI) o 25 centres in the UK; 2017-21.o The aims of this head-to head, double-blind, cross-over trial are to
determine the most clinically beneficial, cost-effective and best tolerated Treatment Pathway amongst: amitriptyline supplemented with pregabalin, duloxetine supplemented with pregabalin and pregabalin supplemented with amitriptyline, for patients with DPNP.
Pain. 2016;157(5):1132-45.
Detection Thresholds Pain Thresholds
Wind-up, Allodynia
Demant DT et al. Pain. 2014;155(11):2263-73.
Effect of Oxcarbazepine in Peripheral Neuropathic Pain Depends On Pain Phenotype:
NNT 13
NNT 3.9
Chan
ge T
OTA
L PA
IN (N
RS 0
-10)
0 1 2 3 4 5 6
1
0
-1
-2
-3
-4
Week0 1 2 3 4 5 6
Week
Irritable nociceptor: preserved small fiber function (cold, warm, pinprick) , hyperalgesia
Non-irritable nociceptor (deafferentation or degenerative type): dominated by sensory loss
Irritable nociceptor (n=31)Non-irritable nociceptor (n=52)
Placebo-controlled Phenotype-stratified (QST) Study
Clinical Pharmacology & Therapeutics, Vol. 97 Number 2, February 2015.
Human surrogate model
Pain generating mechanisms/Symptoms
New therapeutic agents
Baseline profiling Randomization
Drug
Placebo
Endpoint VAS/Effect
on symptomsRetrospective analysis of
responders
Baseline profiling Stratification/ Randomization
Endpoint VAS/Effect
on symptoms
Drug Subgroup A
Placebo
Drug Subgroup B
DPN, diabetic peripheral neuropathy
Conclusions4
Preventing and Managing Diabetic Neuropathy
Pain. 2016 Feb;157 Suppl 1:S72-S80.
fMRI, functional magnetic resonance imaging; CNS, central nervous system
Diffusion Tensor Imaging/Tractography
Volumetric measures
Conclusion (1): Advanced MRI → Paradigm Shift
Resting fMRI
Task fMRI/ Perfusion Imaging
Magnetic Resonance Spectroscopy
CNS Imaging is affording us a new window to study the impact of
diabetes on the nervous system!
• We are diagnosing DPN and painful DPN too late
• Early diagnosis using POCD in a one stop shop“ and treatment essential in order to prevent/halt DPN
• There are no disease modifying treatments for DPN
• Life style intervention, metabolic control and potential disease modifying agents must be started early.
• Current 1st line pharmacological treatments provide partial relief and we need more research is required
Conclusions (2)
Thank You
“Every problem contains within itself the seeds of its own solution.” Stanley Arnold