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Diabetic Peripheral Neuropathy Where are we now?

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.

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Diabetic Peripheral Neuropathy Where are we now?

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  1. Diabetic Peripheral NeuropathyWhere are we now? Mamatha Pasnoor,MD Associate Professor Co-Director of KU Neuropathy Center The University of Kansas Medical Center

  2. 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

  3. 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.

  4. 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

  5. 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

  6. NORTH AMERICA AND SOUTH AMERICA NEUROPATHY PROJECT M Pasnoor, S. Khan, R. Barohn (2005)

  7. DIABETIC NEUROPATHY CLASSIFICATION I.Symmetric Polyneuropathies: • Relatively fixed deficits: • Distal sensory polyneuropathy (DSPN) • Variants: • acute, severe DSPN in early onset diabetes • pseudosyringomyelic neuropathy • pseudotabetic neuropathy • Autonomic neuropathy • Episodic symptoms: • Diabetic neuropathic cachexia (DNC) • Hyperglycemic neuropathy • Treatment-induced diabetic neuropathy • II. Asymmetric/Focal and Multifocal Diabetic Neuropathies: • Diabetic lumbosacral radiculoplexopathy (DLSRP; Bruns-Garland syndrome; diabetic amyotrophy; proximal diabetic neuropathy) • Truncal neuropathies (thoracic radiculopathy) • Cranial neuropathies • Limb mononeuropathies

  8. PATHOGENESIS • Metabolic: Production of destructive metabolic products: Activation of aldose reductase pathway with increased sorbitol levels in nervous tissue • Protein glycation: Glycosylation of nervous tissue structural proteins inactivates and destroys the nervous tissue • Vascular theory: Glucose deposited in basement membrane decreased permeability  build up of toxic metabolites • Microvascular/ Ischemic theory- Thickening of vessel wall , endothelial hypertrophy, leading to ischemia

  9. Spectrum of possible pathophysiologic causes of various diabetic neuropathies PATHOGENESIS Spectrum of possible pathophysiologic causes of various diabetic neuropathies

  10. PATHOLOGY

  11. 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

  12. 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

  13. 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

  14. 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

  15. DIAGNOSIS • INTRAEPIDERMAL NERVE FIBER DENSITY Our study: 20 diabetics, 14 controls, 9 CSPN IENF density Mean (fibers/mm)

  16. MANAGEMENT • Slowing progression of the disease • Releiving pain • Managing complication and restoring function • Nerve repair /growth

  17. 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

  18. 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

  19. MANAGEMENT • Slowing progression of the disease • Releiving pain • Managing complication and restoring function • Nerve repair /nerve growth

  20. 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

  21. 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 ClinPharmacol. 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.

  22. 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 ClinPharmacol 2011 Nov;67(11):1131-7

  23. 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

  24. 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 .

  25. 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

  26. 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

  27. 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.

  28. 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

  29. 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

  30. DLX vs PGB in DPN & CSPNMittal 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% Both are probably effective for DPN & CSPN neuropathic pain * Differences NS Int J Neurosci. 2011;121:521-7

  31. 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

  32. 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

  33. 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 • Averagedaily pain score was reduced more in the capsaicin group than in the placebo group (-27.4% vs -20.9%; P = .025) in DPN

  34. 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 • Combo* 2.3 • Well tolerated, most common AE dry mouth esp. with NTP *p<0.05 vs. others Lancet. 2009 Oct 10;374(9697):1252-61

  35. 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

  36. 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

  37. 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…

  38. 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

  39. 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).

  40. MANAGEMENT: ASSISTIVE DEVICES • Transcutaneouselecrical 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

  41. 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)

  42. CONTROVERSIAL INTERVENTIONS • Interventional / regional anesthesia: odd choice for diffuse neuropathy • Spinal cord neuro-stimulation is experimental • Peripheral nerve decompression trial completed, results?

  43. MANAGEMENT • Slowing progression of the disease • Releiving pain • Managing complication and restoring function • Nerve repair /growth

  44. 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

  45. 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 frequency, type, intensity • Pre-diabetic neuropathy: 1 year diet/exercise counseling, single group (Smith 2006) r=-0.4

  46. DIABETIC RESEARCH • Collaborative effort by three researchers • Douglas Wright, PhD Professor, Anatomy Department • Patricia Kluding, PT, PhD, Associate Professor, Physical Therapy and Rehab Science • MamathaPasnoor, 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

  47. 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

  48. 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

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