1. Painful Diabetic Neuropathy Dr Michelle Spruce University of Southampton United Kingdom

2. The Progress: From Phlogiston to Pain

3. Definition of Pain “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” IASP (1979) “..what the patient says hurts” Mcaffery (1988) But sometimes the patient does not say!!

4. Identifying Pain

6. Normal Pain Perception Normal warning system Nociceptors bare sensory nerve endings Myelinated A delta or thinner unmyelinated C fibres Somatic pain: skin, muscle and joints Superficial: sharp or pricking Deep: burning, itching, aching

7. Normal Mechanisms of Pain Perception Nociceptive Stimulus Transduction BRAIN THALAMUS SPINAL CORD Higher centre activation DESENDINGDESENDING INHIBITIONINHIBITION C A delta Neuronal transmission

8. Epidemiology of Diabetes 1 million GBP’s per hour 1 100 million people world wide 2 Up to 60% develop polyneuropathy 3-6 43% - 53% experience painful symptoms 7-8 Challenging complications “I have tried everything for the pain and I just don’t know what to do”

9. Painful Diabetic Neuropathy Understanding of Pain = “alarm bell” response Chronic, persistent pain offering no overt physical cause Evoking physical and emotional response Leading to reduced quality of life, sleep depravation, cognitive performance Afferent and efferent nerve fibres types may not e uniformly affected 9-10

10. Definitions of Neuropathic Pain Adapted from Haigh RC, Blake DR. Understanding pain. Clin Med 2001; 1:44-48 Pain TerminologyCurrently accepted definitions Referred painPain in area far removed from site of tissue injury Phantom painPain in absent part of body - removed (surgically or congenitally) AllodyniaNon-noxious stimulus perceived as painful HyperalgesiaExaggerated pain produced by noxious stimulus SensitisationReceptor response to stimulus in more intense manner HyperpathiaIntense pain with repetitive stimuli Stimulus evoked painAlteration to sensory neurones, i.e. Following damage

11. Proposed alterations to pain transmission: Gating Theory

12. Gating Theory Melzack and Wall 1965 Pain “gate” located in dorsal horn of spinal cord Impulses from C fibres and A beta fibres enter the cord If impulses from C fibres (pain) out number A beta fibres (light touch/pressure) = –GATE OPEN & PAIN TRANSMITTED Gate closed by enkephalin releasing inter-neurones 11

13. Gating Theory: Alteration Diabetes appears to alter homeostatic process 12 A beta fibres switch to synthesis of substance P following injury Substance P - strengthens pain signal Capsaicin Light touch stimuli sufficient to open gate Define this type of pain?

14. Mr Higgins Type 2 Diabetes Diagnosed 2002 Aged 57 C/o Constant pain to feet, burning pain, putting on shoes and socks hurts, bed linen etc Anxious about you touching his feet Struck by lighting in 2000

15. Spinal Rewiring Theory

16. Spinal Rewiring

17. Mrs Clarke Type 2 Diabetes – Diagnosed 2005 Lesser toe amputation Reporting pain to amputated toes or feeling like they were still present “feel like they are big fat toes, a bit like sausages”

18. Central Spinal Sensitisation

19. Nerve stimulation leads to (N- methyl-D-aspartate) NMDA receptor stimulation Post synaptic membrane, dorsal horn

20. Central Spinal Sensitization “Spinal wind-up” –Can be defined as a continuous increased excitability of central neuronal membranes with persistent potentiation. –Chronic learnt pain pathways!

21. Mr Ronaldson Type 2 diabetes, neuropathic History of ulceration to 1 st MPJ (right foot) Resolved after 32 days Now reporting pain to previously ulcerated site No sign of breach of skin or foreign body What is happening?

22. Ectopic Electrical Impulses Diabetes leads to damage of nerve axon Increase in sodium channels Generation of ectopic electrical impulses Hyperexcitability of nociceptors in DRG Neighbouring uninjured axons also effected Distal damage of axon & proximal hyperexitability = clinically painful but insensate leg!

23. Mrs Young Newly diagnosed type 2 Initially placed upon metformin but HbA1c was still 10% Now c/o burning, lancinating pains to legs, worse at night Recently put on weight but being very strict with her diet! What has happened?

24. Metabolic Control Rapid changes in glycaemic control linked to DPN Boulton et al (1982) infusion of insulin reduced painful symptoms Tight glycaemic control possible trigger – painful neuritis Tesfaye et al., (1996) endoneurial hypoxia linked to increased skin temperature and b.flow in DPN

26. Pharmacological Management Antidepressants etc amitryptyline & trimipramine Often first line treatment, since 1970’s NCCCC, 2008 still recommends as fist line choice Thermal, mechanical & electrical stimuli Side effects: blurred vision, dry mouth, etc What % do you think report ineffective pain relief? 2-3 week delay in achieving effective dose Block NMDA receptors (spinal windup) Review 4-6 weeks

27. Selective serotonin re-uptake inhibitors Useful for those who can’t tolerate TCA’s Mode of action based upon serotonin is mediator of analgesia Results of studies are mixed Evidence that paroxetine reduces lancinating pain.

28. Anti-convulsants Gabapentin first to be licensed for NP Inhibits voltage-activated sodium channels and calcium channels Works at spinal cord level Effective in heat hyperalgesia and mechanoallodynia in animal models Studies shown significant pain relief and QOL at dose of 1800 mg/day Small study indicated no significant efficacy than amitriptyline but less side effects Rapid titration may increase risk of CNS side-effects

29. Anti-convulsants Pregabalin Phenytoin Cabamazepine Lamotrigine Topiramate

30. Topical Treatments Capsaicin – extract chilli peppers Depletes substance P from afferent nerve Side effects: burning, tingling, erythema stinging May get worse before gets better Maximum therapeutic effect delayed 4-6 weeks Regular application – 4 times per day

31. Topical Treatments: Op-site Film dressings – some efficacy on open wounds RCT by Foster demonstrated reduction using VAS & QOL data Potential barrier to exogenous stimuli Helpful in relieving allodynia

32. NMDA Antagonists Dextromethorphan –Low affinity NMDA receptor blocker –Limited studies Ketamine –Have preventive analgesic effects –May reduce opioid requirements in opioid tolerant patients –May help with allodynia or hyperalgesic states

33. Narcotic Analgesics 2 key studies – 210mg/day split doses better than placebo in pain reduction Tramadol provided long term reduction in pain Number of subjects attrition due to poor pain relief or adverse events 14.5% Last line treatment – severe painful neuropathy Side effects: nausea, vomiting & constipation

34. NSAID’s & Neurokinin receptor antagonists NSAID’s Limited evidence – 1 study Demonstrated positive outcomes – VAS Neurokinin receptor antagonists Lanepitant Modulates substance P binding Successful in animal models for persistent pain Used as adjunct therapy with NMDA antagonists

35. Non-Pharmacological Management Transcutaneous electrical nerve stimulation (TENS) Mode of action linked to stimulation f endogenous opioids at SC level, gating theory Portable, topical Acupuncture Limited studies but suggest safe and effective Counselling and psychological treatments

36. Brief Overview: Selection of Treatment Pain controlled with simple analgesia Offer local measures and initiate a trial does of TCA’s – review every 4-6 weeks Pain uncontrolled or titration side effect limited Initiate trial of gabapentin, titrate dose, review 4-6 weeks Pain uncontrolled Consider third agent – pregabalin, review 4-6 wks Pain uncontrolled Initiate opioid therapy Note: consider referral to specialist at earliest point

37. Conclusion The Weeping Woman – intensity of pain communicated by the face.