DIABETES AND PAINHongbiao (Hank) Liu MD PhDLuna 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 ANIMALRESEARCH) 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
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 DCruz, 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 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
A particular slide catching your eye?
Clipping is a handy way to collect important slides you want to go back to later.