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

Late diagnosis of DPN1

Peripheral biomarkers of DPN and painful DPN2

Central biomarkers of DPN and painful DPN3

Management of DPN4

Conclusions5

Late diagnosis of DPN1

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]

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

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

Peripheral biomarkers of DPN and painful DPN2

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

Total cholesterol

Triglycerides

Diabetes duration

Change in HbA1c

Smoking

Hypertension1.57

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

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

Nav1.7

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.

Central biomarkers of DPN and painful DPN3

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

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

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

IENFD Proximal Thigh Change (fibres/mm)

-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

PKC ß

PGI2EDHF

VasculardysfunctionNerve and ganglion

blood flowEndoneurial hypoxia

Ischemia/reperfusionA-V shunting

Cameron et al., Diabetologia, 2001; 44:1973 –88

PKCßInhibitor

Antioxidantsαα -Lipoic acid

Linoleic acid

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.

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

Pregabalin 300mg/day

DLX 60mg/day:

Pregabalin 600mg/day:

COMBINATION ARM

HIGH DOSE MONOTHERAPYARM

Non Responders (<30% pain relief)

DLX 60mg/day: N=401

Pregabalin 300mg/day:

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

0 4 8Intensive Treatment Period (weeks)

p=0.098

p=0.370

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

0 1 2 3 4 5 6

Week0 1 2 3 4 5 6

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

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

Conclusions4

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

Prof. Solomon Tesfaye MB ChB, MD, FRCP · 2019-05-18 · Preventing and Managing Diabetic...

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