Painful Diabetic NeuropathyDr Michelle SpruceUniversity of SouthamptonUnited Kingdom

The Progress: From Phlogiston to Pain

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!!

Identifying Pain

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

Normal Mechanisms of Pain Perception

Nociceptive Stimulus

Transduction

BRAIN

THALAMUS

SPINAL CORD

Higher centre activation

DESENDING

INHIBITION

C

A delta

Neuronal transmission

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”

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

Definitions of Neuropathic PainAdapted from Haigh RC, Blake DR. Understanding pain. Clin Med 2001; 1:44-48

Pain Terminology Currently accepted definitions

Referred pain Pain in area far removed from site of tissue injury

Phantom pain Pain in absent part of body - removed (surgically or congenitally)

Allodynia Non-noxious stimulus perceived as painful

Hyperalgesia Exaggerated pain produced by noxious stimulus

Sensitisation Receptor response to stimulus in more intense manner

Hyperpathia Intense pain with repetitive stimuli

Stimulus evoked pain Alteration to sensory neurones, i.e. Following damage

Proposed alterations to pain transmission: Gating Theory

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 TRANSMITTEDGate closed by enkephalin releasing inter-

neurones 11

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?

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

Spinal Rewiring Theory

Spinal Rewiring

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”

Central Spinal Sensitisation

Central Spinal Sensitisation• Nerve stimulation leads to

(N-methyl-D-aspartate) NMDA receptor stimulation

• Post synaptic membrane, dorsal horn

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!

Mr Ronaldson• Type 2 diabetes, neuropathic

• History of ulceration to 1st 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?

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!

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?

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

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

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.

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

Anti-convulsants• Pregabalin

• Phenytoin

• Cabamazepine

• Lamotrigine

• Topiramate

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

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

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

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

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

Non-Pharmacological ManagementTranscutaneous 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

Brief Overview: Selection of TreatmentPain 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

weeksPain uncontrolled

• Consider third agent – pregabalin, review 4-6 wks

Pain uncontrolled • Initiate opioid therapy

• Note: consider referral to specialist at earliest point

ConclusionThe Weeping Woman – intensity of pain

communicated by the face.