1. DIABETES AND
PAIN
Hongbiao (Hank) Liu MD PhD
Luna Medical Care

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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 ?

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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)

17. 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

18. 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

19. 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

20. QUESTION
S?

21. REFERENCES
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22. REFERENCES
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