DIABETES AND PAIN

Hongbiao (Hank) Liu MD PhD

Luna Medical Care

DIABETES MELLITUS

Disorder of glucose metabolism Relative or total lack of insulin Results in Lipolysis Gluconeogenesis Glycogenolysis Hepatic conversion of FA’s to ketone bodies

and hyperglycaemia Resultant glycosuria causes polyuria,

polydipsia, XS sodium and potassium loss

DIABETES MELLITUS

Affects 1-2% of population Over 80% are over 80yr old

Classically – type 1 (IDDM) – type 2 (NIDDM) – assoc obesity Complications – Renal, cardiovascular, NEUROPATHY

(peripheral – motor or sensory & autonomic) – can affect cranial nerves, eyes, infection, DKA/HONK, stiff joints

Infection and vascular pathology can be cause of pain

DIABETES MELLITUS Fear of evoked pain can restrict activities Peripheral neuropathies can become complicated

by a variety of comorbid neuropsychiatric conditions inc – sleep disturbance, decreased concentration (distraction by pain), depression/anxiety.

Studies have noted reduced self caring which is important to minimise incidence of secondary complications

Poorer diabetic control seen in diabetic patients with pain

Painful diabetic neuropathy (PDN) prevalent in 10-20 % of diabetics

Possibly acute remitting or chronic (more common) subtypes

DIABETES MELLITUS

Small fibres may be damaged in early stages of diabetes

Causing early impairment of pain and temperature sensations plus autonomic neuropathy

Most common presentation to pain clinic is painful diabetic peripheral neuropathy (DPN)

Classically symptoms progress distal to proximal (usually toes) – often symmetrically

Neuropathic descriptions especially burning Loss of deep tendon reflexes, motor weakness,

muscle atrophy, foot drop, gait disturbance, severe functional losses can all occur over time

PAINFUL DIABETIC NEUROPATHY - PATHOGENESIS

Small nerve fibres more commonly damaged (seen in neurophysiological tests and skin biopsies – small nerve fibre losses/changes)

Abnormalities of small nerve function (neurophysical tests) NOT predictive of pain

QST temperature threshold changes noted in asymptomatic DM patients (also see increased threshold to light touch)

Large fibre changes less dramatic and felt to be less important

Common bilateral symptoms suggest systemic environment rather than local is important

PAINFUL DIABETIC NEUROPATHY - PATHOGENESIS How does small fibre loss/damage result in pain ? C fibre spont firing (upregulation of sodium

channels) ? Altered transmission down larger myelinated

faster conducting fibres ? Spinal interneurones with reduced input altering

how remaining inputs (AB) are processed and transferred in dorsal horn

? DRG changes ? Other central changes Reduced GAGA-ergic and monoaminergic

influences (both inhibitory) Changes in glial cells Psychological dysfunction also common

PAINFUL DIABETIC NEUROPATHY - PATHOGENESIS Central changes also occur Activation of brain areas associated with pain

processing , inc (from rat studies)... Secondary somatosensory cortex Ventrobasal thalamic nuclei Basolateral amygdala Reduced activity in habenular nuclei in PAG Other rat study found reduced N acetyl aspertate

in thalamus Abnormal firing of thalamic neurons previously

seen in PDN Are central changes primary or secondary to

peripheral changes ?

PAINFUL DIABETIC NEUROPATHY - PATHOGENESIS Evidence of hyperglycaemia and impaired insulin

(? more important) being involved in pathogenesis

Mechanism not fully determined Some evidence that initial nerve damage less

severe in type 2 DM (insulin resistance as opposed to reduced amount –hyperglycaemic stress similar in both)

Plus changes in type 1 – more paranodal nerve damage

Oxidative stress and cytokines may be involved Hyperglycaemia contributes to this plus it may

affect function or synthesis of numerous proteins which have numerous roles and could easily be implicated both centrally and peripherally

PAINFUL DIABETIC NEUROPATHY - PATHOGENESIS

Insulin may be important for nerve function Insulin possibly has a neuroprotective role in

experimentally induced oxidative stress Again insulin affects numerous metabolic

processes including metabolism of potential neurotransmitters and effects both direct and indirect on cell signaling

Several animal studies showing benefits by affecting (direct or indirect) oxidative stress/free radicals/inflammation, etc

PAINFUL DIABETIC NEUROPATHY – PATHOGENESIS (SOME ANIMAL RESEARCH)

Neurotrophin 3 preventing activation of axonally transported stress activated protein kinase

Low dose poly (ADP-ribose) polymerase inhibitor reverses early diabetic peripheral nerve changes (but globally affects DNA transcription) – acts to reduce free radicals

RAGE (receptor for advanced glycation end products) seems to be activated and possibly has central role in sensory neural dysfunction (NF-KB, IL-6, TNF) may all be involved centrally

DIABETES MELLITUS

Can get unusual presentations of diabetic neuropathies

Burning mouth syndrome (absence of obvious pathology, DM, oral/perioral pain)

You can get an acute painful perineuropathy upon achieving strict glycaemic control – symptomatic improvement with slight laxing of BM control

Muscle infarction is rare presentation of pain (usually thigh) – effects on blood flow cause inflammation/cell damage/oedema – increase pressure – reduced blood flow (akin to compartment syndrome) : consider if atraumatic swelling of limb

DIABETES MELLITUS TREATMENT

Treatments are limited Near impossible to “cure” established pain Aim for normoglycaemia – some evidence it

may reduce PDN incidence Severe fluctuating serum glucose

concentrations may have adverse effects on neuropathic pain

Paracetamol and NSAIDS – poorly effective

DIABETES MELLITUS TREATMENT Antidepressants TCA’s have more balanced effect on different

central inhibitory neurotransmitters (cf SSRI, etc) – may account for being more effective

Also effect NMDA receptors and Na channel effects Biggest SE’s = drowsiness and lethargy NNT (PDN) – 1.3, RR 12.4 Evidence for duloxetine and venlafaxine (serotonin

and norepinephrine reuptake inhibition) being better than placebo – well tolerated, but not as effective as TCA’s

Venlafaxine NNt (PDN) – 3.1, RR 2.2 Duloxetine has metabolic effects to increase

glucose and lipids but this doesn’t seem to be problematic

DIABETES MELLITUS TREATMENT

Anticonvulsants Insufficient data to calculate NNT for

carbamazepine – small studies suggest benefit Gabapentin – GABA derivative, but works at

alpha2delta voltage gated calcium channels NNT 2.9 (PDN), NNH (minor) 3.7 NNH (major) – insignificant Consider pregabalin if gabapentin not tolerated

Lamotrigine – no evidence, other anticonvulsants better

DIABETES MELLITUS TREATMENT Opiates Controversial use in neuropathic pain Cochrane quote modest effect in intermediate

term studies (need longer term evidence) Possible effects on spontaneous neuropathic pain

and reducing dynamic and cold induced allodynia No effect on static allodynia or threshold of heat

or mechanical allodynia

Tramadol may have some benefit (dual role) Oxycodone – lower incidence of intolerable opiate

SE’s cf morphine One study suggests synergistic effect of

morphine and gabapentin (but problems with SE’s)

DIABETES MELLITUS TREATMENT

Mexilitine (class 1B antiarrhythmic) Only 2 studies show benefit over placebo

(dose less than antiarrhythmic dose) Need regular ECG monitoring Not advocated for long term use in PDN

NMDA receptor antagonists – e.g ketamine Small studies, some evidence of effect

Topical nitrate – 2 studies show improved symptoms

DIABETES MELLITUS TREATMENT Capsaicin – some evidence of efficacy But seems to induce complete or near complete

epidermal denervation (remember reduced regeneration is associated with PDN)

Acupuncture – possibly some benefit, SE free Poor evidence for other medical therapies

(percutaneous nerve stimulation, static magnetic field therapy, spinal cord stimulator)

Must consider and address psychological and medical comorbidities

Physiotherapy can be important if physical function is poor

DIABETES MELLITUS TREATMENT – POSSIBLE FUTURE TREATMENTS Alpha-lipoic acid : dual role in improving

neuropathic symptoms and modifying natural history of DPN

Acetyl-L-Carnitine : address some of the possible pathological mechanisms of PDN (Na/K ATPase, myoinositol, Nitric Oxide and prostaglangin synthesis, lipid peroxidation)

Benefit in type 1 and 2 DM – electrophysiological testing and analysis of biopsies – benefits at 1 year

Improving pain, nerve regeneration and vibratory perception (effects not limited to small fibres)

Dual action peptides – derived from pancreatic proteins and erythropoeitin – look to address deficient neurotrophic support of peripheral sensory neurones

QUESTIONS ?

REFERENCES 1) Neuropathic pain and diabetes. [Review], Kapur, Dilip, Diabetes/Metabolism Research

Reviews. 19 Suppl 1:S9-15, 2003 Jan-Feb.

2) Differences in Metabolites in Pain-Processing Brain Regions in Patients With ...Lea Sorensen; Philip J Siddall; Michael I Trenell; Dennis K Yue, Diabetes Care; May 2008; 31, 5; ProQuest Medical Library pg. 980

3) Measuring the pain threshold and tolerance using electrical stimulation in patients with Type II diabetes mellitus, Telli & Cavlak, Journal of Diabetes and Its Complications 20 (2006) 308– 316

4) Comfort and support improve painful diabetic neuropathy, whereas disappointment...Gloria Kaye; Alison Okada Wollitzer; Lois Jovanovic, Diabetes Care; Aug 2003; 26, 8; ProQuest Medical Library pg. 2478

5) The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus, Kadiroglu et al, Journal of Diabetes and Its Complications 22 (2008) 241– 245

6) Acetyl-L-Carnitine Improves Pain, Nerve Regeneration, and Vibratory Perception...Anders A F Sima; Menotti Calvani; Munish Mehra; Antonino Amato, Diabetes Care; Jan 2005; 28, 1; ProQuest Medical Library pg. 89

7) Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin...Angelika Bierhaus; Karl-Matthias Haslbeck; Per M Humpert; Birgit Liliensiek; ..., Journal of Clinical Investigation; Dec 2004; 114, 12; ProQuest Medical Library pg. 1741

8) Bodily Pain, Poor Physical Functioning, and Poor Glycemic Control in Adults ...Cathy Sinnott; Mary A M Rogers; David Lehmann; Ruth S Weinstock, Diabetes Care; Jun 2005; 28, 6; ProQuest Medical Library pg. 1534

REFERENCES 9) An unexpected cause of muscle pain in diabetes, L Silberstein; K E Britton; F P

Marsh; M J Raftery; D D'Cruz, Annals of the Rheumatic Diseases; Apr 2001; 60, 4; ProQuest Medical Library pg. 310

10) Burning mouth syndrome and peripheral neuropathy in patients with type 1 diabetes mellitus, Moore et al, Journal of Diabetes and Its Complications 21 (2007) 397– 402

11) Dual-action peptides: a new strategy in the treatment of diabetes-associated neuropathy, Tam et al, DDT • Volume 11, Number 5/6 • March 2006

12) Early detection of small-fiber neuropathy in diabetes, Giuseppe Pozzessere; Paolo Rossi; Annarita Gabriele; Rosalba Cipriani; et al, Diabetes Care; Dec 2002; 25, 12; ProQuest Medical Library pg. 2355

13) C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes, Hideki Kamiya; Weixian Zhang; Karin Ekberg; John Wahren; Anders A F Sima, Diabetes; Dec 2006; 55, 12; ProQuest Medical Library pg. 3581

14) Concurrent activation of the somatosensory forebrain and deactivation of periaqueductal gray associated with diabetes-induced neuropathic pain, Paulson et al, Experimental Neurology 208 (2007) 305–313

15) The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy, Hoybergs & Meert, Neuroscience Letters 417 (2007) 149–154

16) The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes, Lea Sorensen; Lynda Molyneaux; Dennis K Yue, Diabetes Care; Apr 2006; 29, 4; ProQuest Medical Library pg. 883

17) Subclinical pain and thermal sensory dysfunction in children and adolescents with Type 1 diabetes mellitus, Abad et al, 2002 Diabetes UK. Diabetic Medicine,19, 827–831

REFERENCES 18) Painful Diabetic Neuropathy, Veves et al, American Academy of Pain Medicine 1526-

2375/08/$15.00/660 660–674

19) Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Evaluation of Functional Outcomes, Armstrong et al, pain medicine, Volume 8•Number 5•2007

20) Impaired Insulin Signaling as a Potential Trigger of Pain in Diabetes and Prediabetes, Dobretsov et al, Insulin Signalling and Pain, 95-105

21) Abdominal pain in a man with diabetes, Wong and Steiger, Journal compilation © 2008 Diabetes UK. Diabetic Medicine,25, 882–887

22) The natural history of chronic painful peripheral neuropathy in a community diabetes population, Daousi et al, Journal compilation © 2006 Diabetes UK. Diabetic Medicine,23, 1021–1024

23) Pre-perceptual pain sensory responses (N1 component) in type 1 diabetes mellitus, Rossi et al, NeuroReport Vol 13 No 8 12 June 2002 1009 – 1012

24) Enhanced activation of axonally transported stressactivated protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3, Middlemas et al, Brain (2003), 126, 1671±1682

25) Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor–Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy, Li et al, DIABETES, VOL. 54, MAY 2005, 1614-1622

26) Oxidative Stress in the Pathogenesis of Diabetic Neuropathy, Vincent et al, Endocrine Reviews, August 2004, 25(4):612–628

27) The Effect of Chronic Pain on Diabetes Patients' Self-Management, Sarah L Krein; Michele Heisler; John D Piette; Fatima Makki; Eve A Kerr, Diabetes Care; Jan 2005; 28, 1; ProQuest Medical Library pg. 65

REFERENCES 28) Neuropathy Differs in Type 1 and Type 2 Diabetes. SIMA, ANDERS A.F a; KAMIYA,

HIDEKI, Annals of the New York Academy of Sciences. 1084(1):235-249, November 2006.

29) Current and Future Strategies for the Management of Diabetic Neuropathy.[Review], Malik, Rayaz A, Treatments in Endocrinology. 2(6):389-400, 2003.

30) Peripheric and automatic neuropathy in children with type 1 diabetes mellitus: the effect of L-carnitine treatment on the peripheral and autonomic nervous system. Uzun N, Sarikaya S, Uluduz D, Aydin A, Electromyography & Clinical Neurophysiology. 45(6):343-51, 2005 Sep-Oct.

31) Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes. Murakawa et al, Diabetes/Metabolism Research Reviews. 21(5):448-58, 2005 Sep-Oct.

32) Cochrane database