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Diabetic Peripheral Neuropathy

Where are we now?


Mamatha Pasnoor,MD
Associate Professor
Co-Director of KU Neuropathy Center
The University of Kansas Medical Center
DIABETIC NEUROPATHY

“ the presence of symptoms and/or signs of peripheral


nerve dysfunction in people with diabetes after the
exclusion of other causes”

Boulton AJM, Gries FA, Jervell JA: Guidelines for the diagnosis and outpatient
management of diabetic peripheral neuropathy. Diabetic Med 15:508–514, 1998
HISTORY
 1550 BC: First report of diabetes (disease with polyuric state), written in
hieroglyphs, found in a grave in thebes by Egyptologist, Ebers. Treated with
decoction of bones, wheat, grain, grit, green lead and earth.

 2nd century AD Areteaus used term “dia” ( to pass through), “betes” ( a water
tube) for kidney disease

 5th century AD Chen Chuan in china noticed polyuria and sweet-tasting urine.
Recommended abstinence from wine, salt and sex

 Sushruta in India also noted that the urine of diabetics tastes “like honey”. He
also seemed to describe for the first time, the symptoms of
neuropathy…burning in the palms and soles.
HISTORY
 Most of initial reports from the Orient.

 In 18th century Western physicians started studying diabetes and


complications

 19th century (de Calvi, Pavy) established link between DM and


neuropathies

 1921-S Fagerberger reported microvascular pathology


EPIDEMIOLOGY- DIABETIC NEUROPATHY
 PN affects 2.4 to 7% of the population
 The Foundation For Neuropathy estimates 40 million affected

 CDC National Diabetes Fact Sheet 2011:


– 25.8 million diabetics
– 60-70% mild to severe neuropathy forms
– 35% of U.S. adults aged > 20 years pre-diabetes
 Time of diagnosis: 8% of non-insulin dependent diabetics compared with 2% of
age/sex matched controls have neuropathy
 Any given time:
– 34% of IDDM/26% of NIDDM have distal symmetric polyneuropathy
– 26.4% of diabetic patients have painful neuropathy
 Prevalence at 10 years F/U: 42% among diabetics
 Prevalence at 30 years : 58% of patients have distal symmetric polyneuropathy
NORTH AMERICA AND SOUTH AMERICA
NEUROPATHY PROJECT
M Pasnoor, S. Khan, R. Barohn (2005)

Major category NA(No. of pts)(%) SA(No. of pts)(%)

Total no. of cases 1090 1034


Immune mediated 215 (19.7%) 191 (18%)
Diabetic 148 (13.5%) 236 (23%)
Hereditary 292 (26.7%) 103 (10%)
Infect./inflamm. 53 (4.8%) 141 (14%)
Syst./metab./toxic 71 (6.5%) 124 (12%)
Cryptogenic 311(28.5%) 239 (23%)
DIABETIC NEUROPATHY CLASSIFICATION
I.Symmetric Polyneuropathies:  II. Asymmetric/Focal and
Multifocal Diabetic
Neuropathies:
 Relatively fixed deficits:
 Diabetic lumbosacral
 Distal sensory polyneuropathy (DSPN)
radiculoplexopathy (DLSRP;
 Variants: Bruns-Garland syndrome;
 acute, severe DSPN in early onset diabetic amyotrophy; proximal
diabetes diabetic neuropathy)
 pseudosyringomyelic neuropathy  Truncal neuropathies (thoracic
 pseudotabetic neuropathy radiculopathy)
 Autonomic neuropathy  Cranial neuropathies
 Limb mononeuropathies

 Episodic symptoms:
 Diabetic neuropathic cachexia (DNC)
 Hyperglycemic neuropathy
 Treatment-induced diabetic neuropathy
PATHOGENESIS

1) Metabolic: Production of destructive metabolic products: Activation of


aldose reductase pathway with increased sorbitol levels in nervous tissue
2) Protein glycation: Glycosylation of nervous tissue structural proteins 
inactivates and destroys the nervous tissue
3) Vascular theory: Glucose deposited in basement membrane  decreased
permeability  build up of toxic metabolites
4) Microvascular/ Ischemic theory- Thickening of vessel wall , endothelial
hypertrophy, leading to ischemia
PATHOGENESIS

Spectrum of possible pathophysiologic causes of various diabetic


neuropathies
PATHOLOGY
SYMPTOMS/SIGNS
 SENSORY:
 Negative & positive sensory symptoms: Numbness, tingling,
burning pain
 Worse at rest. All painful neuropathic symptoms prone to
nocturnal exacerbation
 Stocking-glove pattern
 Imbalance / impaired JPS
 Motor:
 Distal weakness mild or absent
 Foot muscle atrophy
 Not disabling
 Not proximal
 Absent or reduced tendon reflexes
DIABETIC NEUROPATHY
 Is it Diabetic Neuropathy?
• Exclude all other causes of neuropathy
–nutritional deficiencies
–paraneoplastic
–toxic eg alcohol
–infectious eg HIV

Highest yield of abnormality (AAN Practice parameters, 2008)


Blood glucose
Serum B12 with metabolites
Serum protein immunofixation electrophoresis
DIAGNOSIS
 Bedside assessment :
Pin, light touch, vibration, proprioception, strength, reflexes
using safety pin, cotton, tuning fork , reflex hammer
 Semi-quantitative measures
Nylon Monofilament Perception
 Screening tests:
Michigan Neuropathy Screening Instrument.
Visual analog score
Total Neuropathy Score
Utah Early Neuropathy Scale
…Many more scales have been developed for assessment
DIAGNOSIS
 NCS : distal symmetric axonal loss with mild conduction slowing in
NCV & F-wave proportional to axon loss

 EMG : abnormal spontaneous activity and large amplitude MUPs

 Rarely, NCS/EMG are normal and diagnosis of small fiber neuropathy


is confirmed by:
 QST
 IENF density analysis
 QSART (Quantitative sudomotor autonomic reflex testing)
 Autonomic testing
 Skin biopsy
DIAGNOSIS
 INTRAEPIDERMAL NERVE FIBER DENSITY

Our study: 20 diabetics, 14 controls,


9 CSPN
IENF density Mean (fibers/mm)
Diabetic Controls CSPN
5.4(6.7) 15.7(17.8) 4.8(3.18)
MANAGEMENT
 Slowing progression of the disease
 Releiving pain
 Managing complication and restoring function
 Nerve repair /growth
MANAGEMENT : SLOWING PROGRESSION
 Target range of blood sugar levels:
≤ 59 : 80-120 mg/dl
≥ 60 : 100-140 mg/dl
• Blood pressure control
• Healthy eating plan
• Plenty of physical activity
• Maintain Healthy weight
• Stop smoking
• Avoid alcohol
MANAGEMENT
 Insulin therapy:
 No randomized, controlled trials of intensive insulin therapy
 Observational studies suggest that stable glycemic control is of
the greatest importance
 One study using continuous glucose monitoring confirmed that
painful symptoms were associated with erratic blood glucose
control (Oyibo S et al. Diabetic Med 2002)
 No evidence that patients well controlled on oral hypoglycemic
agents will benefit in terms of pain relief by transferring to
insulin
MANAGEMENT
 Slowing progression of the disease
 Releiving pain
 Managing complication and restoring function
 Nerve repair /nerve growth
MANAGEMENT
 Simple physical treatments,
 Use of a bed cradle to lift the
bed clothes off hyperaesthetic
skin
 Advice on suitable footwear may
also be provided.
 Simple analgesics or anti-
inflammatory agents
ANTIDEPRESSANTS : TCA’s
 TRICYCLIC ANTIDEPRESSANTS
 Effects on sodium channels and the Nmethyl-D-aspartate (NMDA)
receptors.
 >9 TCA and/or SSRI clinical trials in DPN or PHN
 Tricyclic antidepressants (TCAs) highly effective: amitriptyline,
nortriptyline and desipramine
 Br J Clin Pharmacol. 1990 Nov;30(5):683-91. Neurology. 2002
Oct 8;59(7):1015-21
 TCA effect independent of depression comorbidity
̶ Neurology 1987 Apr;37(4):589-96

 Side effects: dry mouth, blurred vision, cardiac arrhythmias, sedation,


urinary retention, constipation, and postural hypotension.
ANTIDEPRESSANTS: SSRI’s
 Selective serotonin reuptake inhibitors (SSRIs) less effective than
TCAs:
 Fluoxetine no different than placebo in DPN
 N Engl J Med 1992 May 7;326(19):1250-6.
 Paroxetine less effective than imipramine in DPN
 Pain 1990 Aug;42(2):135-44.
 Escitalopram rs6318 SNP in the serotonin receptor 2C gene
associated with 75% moderate or better pain relief
 Eur J Clin Pharmacol 2011 Nov;67(11):1131-7
ANTIDEPRESSANTS: SNRI VENLAFAXINE
 Increases synaptic serotonin/NE (SNRI) by inhibiting reuptake
 RCT: ER significantly reduces pain intensity in DPN
 Pain 2004 Aug;110(3):697-706

 Doses of 150-225 mg a day, not 75 mg


 Useful as add on to GBP in DPN: improved pain, QOL, sleep and
mood
 J Clin Neuromuscul Dis 2001 Dec;3(2):53-62

 112.5 mg bid may be as effective as imipramine 75 mg BID in a 3-


way crossover, 4-wk RCT in DPN (n=15) and non-diabetic cases
(n=17, CSPN = 11)
 Neurology 2003 Apr 22;60(8):1284-9

 Relatively well tolerated; side effect of nausea and somnolence


ANTIDEPRESSANT SNRI : DULOXETINE
 First FDA approved agent DPN (also approved for
fibromyalgia)
 SNRI released in Fall 2004 with higher, more balanced
affinity for NE/5HT reuptake sites
 Effective at 60 and 120 mg/d not 20 mg/d
 Higher AE incidence with 120 mg dose

Pain. 2005;116(1-2):109-1 Pain Med. 2005;6(5):346-56

.
Duloxetine
 Adverse events (largely dose-dependent)
 Nausea, somnolence, dizziness, constipation, dry mouth
 Drug interactions
 MAOIs (wait 14 days)
 TCAs, Phenothiazines, Type 1C antiarrhythmics, Quinolone
antibiotics and Cimetidine
 Precautions: closed-angle glaucoma and hepatotoxicity
 Black box warnings: suicide risk
GABAPENTIN: DPN
 RCT 8 wk in 165 DPN patients GBP vs PBO:
 Mean daily pain scores lower in GBP group (p<.001)
 26% pain-free vs. 15% on placebo at 8 wks
 Improved quality of life & sleep
 JAMA 1998;280:1831-36

 GBP vs. amitriptyline cross-over study in DPN


 No significant difference
 Arch Intern Med 1999;159(16):1931-7

 Mechanisms of action: binds to 2 subunit of presynaptic voltage-


dependent Ca channel
 Also increases CNS levels of GABA
ANTICONVULSANT: PREGABALIN
 Approved on 12/31/04:
̶ DPN 50-100 mg TID
̶ PHN 75-300 mg BID
̶ Fibromyalgia 75-225 mg BID
Neurology 2004;63:2104-10 Curr Med Res Opin. 2006;22:375-84.
ANTICONVULSANTS: PREGABALIN
 Similar mechanism as gabapentin
 Initiate at therapeutic dose, onset of action by day 2-3
 Am J Ther 2010;17(6):577-85

 Linear pharmacokinetics across therapeutic doses


 DPN adverse events on 150, 300 mg & 600 mg daily:
 Dizziness (9, 23 & 29%)
 Somnolence (6, 13 & 16%)
 Peripheral edema (6, 9 & 12%)
 Weight gain (4, 4 & 6%)
 Dry mouth (2, 5 & 7%)
 Blurry vision (1, 3 & 6%)
 SAE: suicide risk
LAMICTAL
 DPN RCT vs PBO, n=59
 Numerical pain scale reduction 6.4 to 4.2 and with
PBO 6.5 to 5.3 (p < 0.001)
 Effective at doses of 200 – 400 mg daily
 Neurology 2001;57:505-9
DLX vs PGB in DPN & CSPN
Mittal M, Pasnoor M, Mummaneni RB, Khan S, McVey A, Saperstein D, Herbelin L,
Ridings L, Wang Y, Dimachkie MM, Barohn RJ

 Retrospective chart review


 N=143; both drugs at different times n = 51, only one n= 92
 Majority DPN & CSPN
 Overall responders: DLX 41% PGB 48%
 Discontinuation DPN: DLX 66%, PGB 59%
DPN & DLX PGB
CSPN (59 mg) (217 mg) Both are probably
effective for DPN &
Much 21% 33%
Improved
CSPN neuropathic pain
Adverse 38% 30%
events

* Differences NS
Int J Neurosci. 2011;121:521-7
OPIOD: TRAMADOL IN DPN
• Centrally-acting:
̶ Binds μ-opioid receptors
̶ Weak inhibitor of NEP/5HT reuptake
• RCT tramadol (n=65; 50-400 mg) vs.
PBO (n= 66):
̶ Effective in DPN
̶ Mean dose 210 mg/d
̶ No effect on sleep
̶ AEs: nausea, constipation,
HA & somnolence
Neurology 1998;50:1842
ANALGESICS/ OPIOD: Oxycodone CR

• RCT n=159
• Dose 10 mg BID increased Q 3 d to maximum 60
mg BID
• Primary efficacy was pain intensity at days 28 & 42
• Results at mean dose of 37 mg/d (10-100):
̶ Effective in moderate to severe DPN pain
̶ Adverse events in 96% vs. 68% on PBO
• Constipation 42%
• Somnolence 40%
• Nausea 36%
• Dizziness 32%

Neurology 2003; 60:927-934


CAPSAICIN 8% PATCH
 Selectively binds TRPV1 receptor, cation channel
overexpressed in intact nociceptive sensory nerves
 TRPV1 receptor activation at 38 C → high levels of
intracellular calcium & substance P depletion
 Capsaicin cream 0.075-0.1% of limited use
 8% patch : 369 patients Phase III RCT study
 Average daily pain score was reduced more in the capsaicin
group than in the placebo group (-27.4% vs -20.9%; P =
.025) in DPN
GABAPENTIN< NORTRIPTYLINE OR COMBO
 Double-blind, double-dummy, crossover trial, DPN & PHN
 56 patients randomized in a 1:1:1 ratio to receive one of
three sequences of daily oral GBP, nortriptyline, & combo
 Duration of each treatment period 6-week, 45 completers
 Primary outcome mean daily pain at maximum tolerated
dose
 Mean daily pain levels in 45 completers compared to
baseline (5.4):
̶ GBP 3.2
̶ NTP 2.9 *p<0.05 vs. others
̶ Combo* 2.3
 Well tolerated, most common AE dry mouth esp. with NTP

Lancet. 2009 Oct 10;374(9697):1252-61


OTHER MEDICATIONS : NA CHANNEL
BLOCKERS
 Lidocaine: FDA approved for PHN
 Sodium channel blockage, dampening both peripheral nociceptor
sensitization and ultimately central nervous system hyperexcitability
 In an open-label study, the use of a maximum of four patches of 5%
lidocaine per day was associated with relief of neuropathic symptoms
without serious adverse effects. (Barbano RL. Arch Neurol, 2004)
 Side effects: skin rash, edema
 Mexiletine: (Krishnan STM, Diabetes Rep 2004)
 Oral analog of lidocaine
 Not widely used because of side effects and the need for regular
electrocardiogram monitoring with its use
 Side Effects: Nausea, vomiting, dizziness
DPN PAIN :PHARMACOTHERAPY IN 2017
Level A: PGB
Level B: Amitriptyline, DLX, GBP, venlafaxine, Na valproate, Opioids
(tramadol, morphine, oxycodone CR) Capsaicin, isosorbide
dinitrate, Percutaneous electrical stimulation
Level C: Venlafaxine add-on to GBP, Lidocaine patch
Level U: Desipramine or imipramine, fluoxetine, NTP+fluphenazine,
topiramate, vitamins & ALA
Neurology. 2011;76(20):1758-65
Oxcarbazepine & botulinum toxin are effective but low strength of
evidence
No reporting of quality of life
•Neurology. 2017 May16;88(20):1958-1967
PAIN MODULATION
First line drugs:
Anticonvulsants: gabapentin, pregabalin
Antidepressants: tricyclic antidrepressants, duloxetine
Analgesics: tramadol
Topical: lidocaine 5% patch, lidocaine 4% gel, lidocaine
4% cream (OTC)
Second line drugs:
Venlafaxine alone or as add-on to gabapentin
Carbamazepine, Na valproate, lamotrigine, topiramate
Other drugs:
Topicals through compounding pharmacy (ketoprofen,
amitriptyline, tetracaine, lidocaine, cyclobenzaprine,
lioresal, ketamine, gabapentin, carbamazepine)
Opioids: morphine, oxycodone CR, pain contract…
OTHER TREATMENTS
 Alpha lipoic-acid
 Essential cofactor for many enzyme complexes including aerobic metabolism
 Alpha-Lipoic Acid in Diabetic Neuropathy (ALADIN) I study, II and III
 IV treatment showed benefit, oral treatment no significant benefit

 Medical Marijuana in diabetic neuropathy


 A randomized, double-blinded, placebo controlled crossover study (Wallace,
2015)
 16 patients with DPN exposed to 4 single dosing sessions of placebo or to
low (1% tetrahydrocannabinol [THC]), medium (4% THC), or high (7%
THC) doses of inhaled cannabis
 Results: Spontaneous pain score :placebo versus low, medium, and high
doses (P = .031, .04, and <.001, respectively)
 Dose-dependent reduction in diabetic peripheral neuropathy pain in patients
with treatment-refractory pain
 Presently insufficient evidence to suggest this
OTHER TREATMENTS:
NONPHARMACOLOGICAL THERAPIES
 Lifestyle modification, PT & OT
 J Diabetes Complications 2012 Jun 18
 Podiatric care & diabetic orthopedic shoes
 Pain psychologist & Cognitive Behavioral Rx
 Biofeedback/Relaxation Response
 Benson 1975
 Complementary & alternative medicine: acupuncture, supplements, etc.
 Acupunture: Benefits of acupuncture last for up to 6 months
 Reduced the use of other analgesics.(Abusaisha BB.Diabetes. Res Clin Pract
1998)
 Need controlled studies to confirm these observations (challenging to
have control).
MANAGEMENT: ASSISTIVE DEVICES
 Transcutaneous elecrical stimulation (TENS)
 widely used in neuromuscular and pain
syndromes
 Its efficacy is actively debated

 Static magnetic field therapy.


 Sham-controlled crossover study of
magnetic insoles showed some efficacy
(Weintraub, Barohn. Arch Phys Med Rehabil
2003)
 Larger trials are needed

 Bioaxial rotating magnetic therapy


MANAGEMENT: OTHER THERAPIES
 Low-intensive laser therapy (Zinman LH, Diabetes
Care 2004)
 Monochromatic infrared light. (Leonard Dr. Diabetes
2004,)
 Described in small single-center studies
 Require confirmation in larger studies
 Anodyne therapy: FDA-cleared Monochromatic
Infrared Photo Energy (MIRE) therapy (
 Increase local levels of NO thereby increasing
local circulation to nerves and tissues
 No more effective than placebo(Clifft JK et al.
Diabetes Care. 2005)
CONTROVERSIAL INTERVENTIONS
• Interventional / regional anesthesia: odd choice for diffuse
neuropathy
 Spinal cord neuro-stimulation is experimental
 Peripheral nerve decompression trial completed, results?
MANAGEMENT
 Slowing progression of the disease
 Releiving pain
 Managing complication and restoring function
 Nerve repair /growth
MANAGEMENT:
 SB-509 is a formulation of a zinc finger DNA-binding protein
transcription factor (ZFP TF(TM)),
 Upregulate the expression of the gene encoding vascular endothelial
growth factor (VEGF-A)
 VEGF-A has been demonstrated to have direct neurotrophic and
neuroprotective properties
 Negative Study

EXERCISE IN DPN

 2006 Cochrane Review: Exercise improves


glycemic control, reduces adipose and
triglycerides (with/without weight loss)
 14 RCTs with 377 subjects (TYPE 2)
 Intervention: 8 weeks – 12 months (8 or
16 weeks most common); varied r=-0.4

frequency, type, intensity


 Pre-diabetic neuropathy: 1 year
diet/exercise counseling, single group
(Smith 2006)
DIABETIC RESEARCH
 Collaborative effort by three researchers
 Douglas Wright, PhD Professor, Anatomy Department
 Patricia Kluding, PT, PhD, Associate Professor, Physical Therapy and
Rehab Science
 Mamatha Pasnoor, MD, Associate Professor, Department of Neurology
 Working together since 2006
 Initial project – Epidermal skin innervations in diabetic neuropathy vs CSPN
 Pilot project – Safety and efficacy of exercise in diabetic neuropathy
 DPN: 10 weeks supervised aerobic/resistance exercise, single group
(Kluding 2012)
 Decrease pain on VAS
 DPN: 16 weeks supervised aerobic exercise, single group (Kluding 2015)
 No change on BPI-DPN
 Decreased pain interference
ACTIVITY FOR DIABETIC
POLYNEUROPATHY: ADAPT
 Hypotheesis:
 Intervention will: Improve insulin sensitivity, Reduce oxidative stress and
inflammation, Enhanced peripheral nerve regenerative capacity
 Primary goal
 To determine that novel approach to increasing home activity and reduced
sedentary time is an effective therapy for DPN
 Design: Single blind randomized controlled trial
 Methods:
 Compare 18 month standard of care to intensive activity intervention
 Sites : 2, Utah and Kansas
 Total number of subjects to be enrolled=140
 5 year study
ONGOING RESEARCH TRIALS-BASIC
SCIENCE
 Three mouse models: NT-3 transgenic, NT-3 null mutant,
and hereditary mutant mice that undergo degeneration of
NT-3-dependent proprioceptive neurons.
 Studying the trophic support of neurons following
perturbation in vivo, and to explore the extent of NT-3's
therapeutic effects
 Studies designed to define the role of neurotrophins in DPN
To design better treatments for peripheral neuropathies
Ongoing research trials
 Viromed: PI Dr Dimachkie
 A Phase III, Double-blind, Randomized, Placebo-controlled, Multicenter
study
 To Assess the Safety and Efficacy of VM202
 VM202 is a hepatocyte growth factor. In addition to being a potent
angiogenesis factor, this has a potential neurotrophic effect

 Vertex study:
 Nav 1.8 blocker , for small fiber neuropathy
 A Phase 2, Randomized, Double-blind, Placebo-controlled, Study of the
Efficacy and Safety of VX-150
 Dose 1250mg daily oral dose
 Primary end point: Change from baseline in the weekly average of daily pain
intensity on the 11-point numeric rating scale (NRS), as reported in the
daily diary, at Week 6
Thank You
KU NM NEUROPATHY TEAM