Management of Painful Management of Painful Diabetic Peripheral Diabetic Peripheral

NeuropathyNeuropathy

Angus JonesAngus Jones

PlanPlan

Quick caseQuick case

Diabetes associated neuropathies Diabetes associated neuropathies (presentation/investigation)(presentation/investigation)– Acute painful neuropathiesAcute painful neuropathies– Symetrical polyneuropathiesSymetrical polyneuropathies– Focal neuropathiesFocal neuropathies

Management of painful diabetic Management of painful diabetic neuropathyneuropathy

Case PresentationCase Presentation

75 year old lady referred 200775 year old lady referred 2007

T2DM 2000 (rosiglitazone 8mg, A1C 7.5), T2DM 2000 (rosiglitazone 8mg, A1C 7.5),

HTN, AF, hypothyroid (treated), CRF (EGFR 53)HTN, AF, hypothyroid (treated), CRF (EGFR 53)

Bilateral foot pain from 2001Bilateral foot pain from 2001– ‘‘shooting’shooting’– Tingling sensationTingling sensation– NumbnessNumbness– Gradual worsening/numbness more proximalGradual worsening/numbness more proximal– Pain/cramps at nightPain/cramps at night

No back symptomsNo back symptoms

Neck pain (wears neck collar)Neck pain (wears neck collar)

Taking diclofenac/co-codamol for analgesiaTaking diclofenac/co-codamol for analgesia– Pregabalin previously not toleratedPregabalin previously not tolerated

O/EO/E– Profound polymodal sensory loss to knees + in handsProfound polymodal sensory loss to knees + in hands– Absent ankle jerksAbsent ankle jerks– Neck normal ROM/no boney tendernessNeck normal ROM/no boney tenderness

IxIx– Cervical XR spondylitis onlyCervical XR spondylitis only– BloodsBloods

Lfts, CRP, CK, IGgs, folate, B12, RF, TFTs Lfts, CRP, CK, IGgs, folate, B12, RF, TFTs plasmapheresis normal.plasmapheresis normal.

– Nerve conduction studiesNerve conduction studies

Pain clinic reviewPain clinic review– TramadolTramadol– ? Amitryptiline for sedative effect? Amitryptiline for sedative effect– ? Alternative anticonvulsant (carbamazapine)? Alternative anticonvulsant (carbamazapine)– Lumbar sympathectomy ‘trial of’Lumbar sympathectomy ‘trial of’

PlanPlan– Pain clinic referralPain clinic referral– Stop diclofenalStop diclofenal– Imipramine 10mg, titate up doseImipramine 10mg, titate up dose

Acute Painful NeuropathiesAcute Painful Neuropathies

UncommonUncommon

SymmetricalSymmetrical

Two distinct syndromesTwo distinct syndromes– Hyperglycaemic neuropathyHyperglycaemic neuropathy– Acute painful diabetic polyneuropathyAcute painful diabetic polyneuropathy

Hyperglycaemic NeuropathyHyperglycaemic Neuropathy

Poor diabetic control for weeks or monthsPoor diabetic control for weeks or months

Cause unknownCause unknown– Nerve conduction velocity slowedNerve conduction velocity slowed

Uncomfortable sensory symptoms lower Uncomfortable sensory symptoms lower legslegs

Resolves rapidly when hyperglycaemia Resolves rapidly when hyperglycaemia correctedcorrected

Acute Painful Diabetic Acute Painful Diabetic PolyneuropathyPolyneuropathy

Acute and extremely severe neuropathic Acute and extremely severe neuropathic pain with allodyniapain with allodyniaOften follows profound weight loss (usually Often follows profound weight loss (usually in the context of poor diabetes control) or in the context of poor diabetes control) or rapid improvements in control?rapid improvements in control?Clinical findings often mildClinical findings often mildGood prognosisGood prognosis– Complete resolution in 12 to 24 monthsComplete resolution in 12 to 24 months

Chronic Sensory and Autonomic Chronic Sensory and Autonomic Polyneuropathy (DSN)Polyneuropathy (DSN)

Pathogenesis – metabolic and vascular factorsPathogenesis – metabolic and vascular factors– Poor glucose control and/or long duration of DMPoor glucose control and/or long duration of DM– Associated with modifiable CVS risk factorsAssociated with modifiable CVS risk factors

Neurophysiology often mixed sensory/motorNeurophysiology often mixed sensory/motor

Clinical manifestations mostly sensory +/- Clinical manifestations mostly sensory +/- autonomicautonomic– Insidious onsetInsidious onset– Chronic and progressiveChronic and progressive– IrreversibleIrreversible

PresentationPresentation– Asymmetries may occurAsymmetries may occur– Symptoms very variableSymptoms very variable– VariantsVariants

InvestigationInvestigation– Vibration most reliable in predicting neuropathic Vibration most reliable in predicting neuropathic

ulceration and Charcotsulceration and CharcotsMonofilament test also usefulMonofilament test also useful

– Clinical diagnosisClinical diagnosisFormal measurements rarely requiredFormal measurements rarely required

– Nerve conduction may be normalNerve conduction may be normal

– Vibration/thermal threasholdsVibration/thermal threasholds

Autonomic NeuropathyAutonomic Neuropathy

Abnormal autonomic function tests Abnormal autonomic function tests common in patients with features of common in patients with features of sensory neuropathy but symptoms of sensory neuropathy but symptoms of autonomic neuropathy uncommonautonomic neuropathy uncommon– Abnormal autonomic function tests much Abnormal autonomic function tests much

more common than symptomsmore common than symptoms

Parasympathetic then sympatheticParasympathetic then sympathetic– Earliest detectable abnormality loss of heart Earliest detectable abnormality loss of heart

rate variation with breathingrate variation with breathing

Autonomic NeuropathyAutonomic Neuropathy

Symptoms chronic or intermittentSymptoms chronic or intermittent

Abnormal sweatingAbnormal sweating– GustatoryGustatory– Dry neuropathic footDry neuropathic foot– Episodic nocturnal sweatingEpisodic nocturnal sweating

Cardiovascular symptomsCardiovascular symptoms– Postural hypotensionPostural hypotension

Autonomic NeuropathyAutonomic Neuropathy

GIGI– Frequently involved but most patients asymptomaticFrequently involved but most patients asymptomatic– GastroparesisGastroparesis

Failure of pylorus to open +/- reduced peristalsisFailure of pylorus to open +/- reduced peristalsis

Can lead to erratic diabetic controlCan lead to erratic diabetic control

Difficult to diagnoseDifficult to diagnose– Endoscopy essentialEndoscopy essential

– DiarrhoeaDiarrhoea

– ConstipationConstipation

Autonomic NeuropathyAutonomic Neuropathy

Neuropathic BladderNeuropathic Bladder– Mostly asymptomaticMostly asymptomatic– Progressive bladder distension Progressive bladder distension recurrent recurrent

UTIs, overflow incontinence, hydronephrosisUTIs, overflow incontinence, hydronephrosis

Erectile dysfunctionErectile dysfunctionSudden deathSudden death– 10 year mortality of symptomatic autonomic 10 year mortality of symptomatic autonomic

neuropathy 30 to 50%neuropathy 30 to 50%

Focal NeuropathiesFocal Neuropathies

Often unrelated to presence of other diabetic Often unrelated to presence of other diabetic complicationscomplications

Entrapment and compression neuropathiesEntrapment and compression neuropathies– Carpal tunnel, ulnar nerve at elbow, peroneal nerve at Carpal tunnel, ulnar nerve at elbow, peroneal nerve at

neck of fibulaneck of fibula

Cranial nerve palsiesCranial nerve palsies– Abrupt onsetAbrupt onset– Vascular aetiologyVascular aetiology– Recovery 3 - 6 monthsRecovery 3 - 6 months

Focal NeuropathiesFocal Neuropathies

Diabetic Amyotrophy (proxmal motor Diabetic Amyotrophy (proxmal motor neuropathy)neuropathy)– Acute/subacute onsetAcute/subacute onset– PainfulPainful– Wasting/weakness quadracepsWasting/weakness quadraceps

+- hip flexors/abductors/hamstring+- hip flexors/abductors/hamstring

– Weight lossWeight loss– Sensory loss unusualSensory loss unusual

Amyotrophy – managementAmyotrophy – management– Exclude other causes of symptomsExclude other causes of symptoms

MRI lumbosacral area +/- ESR/CXR/USS abdoMRI lumbosacral area +/- ESR/CXR/USS abdo

– Symptomatic/supportive managementSymptomatic/supportive management

Management of Painful Diabetic Management of Painful Diabetic NeuropathyNeuropathy

Could there be another causeCould there be another cause– Wrong diagnosis e.g. nerve route Wrong diagnosis e.g. nerve route

compression/pvdcompression/pvd – Another cause for neuropathy (e.g. b12)Another cause for neuropathy (e.g. b12)

Causes of painful peripheral neuropathyCauses of painful peripheral neuropathy– DmDm– ETOHETOH– HIVHIV– Paraneoplastic syndromesParaneoplastic syndromes– Monocalonal gammopathyMonocalonal gammopathy– Vitamin deficienciesVitamin deficiencies– AmyloidAmyloid– DrugsDrugs– VasculitisVasculitis– Fabry diseaseFabry disease

Management of Painful Management of Painful Diabetic NeuropathyDiabetic Neuropathy

Glycaemic controlGlycaemic control – good control prevents/delays onsetgood control prevents/delays onset – improved control – painful neuropathic improved control – painful neuropathic

symptoms can improvesymptoms can improve

Control large vessel risk factorsControl large vessel risk factorsACE, statinsACE, statins

Management of Painful Diabetic Management of Painful Diabetic Neuropathy - Drug TreatmentNeuropathy - Drug TreatmentTrycyclic antidepressantsTrycyclic antidepressants – proven effectiveness – NNT 3 (cochrane proven effectiveness – NNT 3 (cochrane

17/10/07)17/10/07) – mechanism unclear – not through mechanism unclear – not through

antidepressant propertiesantidepressant properties – Start low (25 to 50mg) and titrate up (to Start low (25 to 50mg) and titrate up (to

150mg if needed)150mg if needed)

Management of Painful Diabetic Management of Painful Diabetic Neuropathy - Drug TreatmentNeuropathy - Drug TreatmentOther antidepressantsOther antidepressants – SNRIs - Venlafaxine – NNT 3,SNRIs - Venlafaxine – NNT 3, - Duloxetine- Duloxetine

AnticonvulsantsAnticonvulsants – Gabapentin (NNT 3.7) and pregabalin Gabapentin (NNT 3.7) and pregabalin

licensedlicensed

OpiatesOpiates – Evidence of effectiveness for tramadol (NNT Evidence of effectiveness for tramadol (NNT

3.8) and oxycodone.3.8) and oxycodone.

Management of Painful Diabetic Management of Painful Diabetic Neuropathy - Drug TreatmentNeuropathy - Drug TreatmentIV lignocaineIV lignocaine – 5mg/kg infusion repeated after 30 minutes 5mg/kg infusion repeated after 30 minutes

effective for up to 3 weeks.effective for up to 3 weeks.

Alpha lipoic acidAlpha lipoic acid – Good evidence for IV preparationsGood evidence for IV preparations

Starflower oil (borage oil)?Starflower oil (borage oil)?

Aldose reductase inhibitorsAldose reductase inhibitors– ‘‘no evidence of benefit’ – Cochrane R/V 2007no evidence of benefit’ – Cochrane R/V 2007

Management of Painful Diabetic Management of Painful Diabetic Neuropathy – Topical TreatmentNeuropathy – Topical Treatment

CapsaicinCapsaicin – Works by depleting substance p from nerve Works by depleting substance p from nerve

terminalsterminals – Topical capsaicin 0.075% ‘sparingly’ TDS/QDSTopical capsaicin 0.075% ‘sparingly’ TDS/QDS – May worsen symptoms for first 2-4 weeksMay worsen symptoms for first 2-4 weeks

GTN spray/patchGTN spray/patchLignocaine 5% patchLignocaine 5% patch

Non Pharmacological Non Pharmacological ManagementManagement

Bed cradle Bed cradle

TENSTENS – AcupunctureAcupuncture

– Electrical chord stimulation Electrical chord stimulation Electrode implanted in thoracic or lumbar epidural space Electrode implanted in thoracic or lumbar epidural space stimulates dorsal columns to block pain transmissionstimulates dorsal columns to block pain transmissionNo placebo studiesNo placebo studies

– Pancreatic transplant Pancreatic transplant

Future Treatment/New DrugsFuture Treatment/New Drugs

Acetyl L carnitine Acetyl L carnitine – 2 RCTs – total 1500 patients ‘significant 2 RCTs – total 1500 patients ‘significant

improvements in pain scores at two years’improvements in pain scores at two years’

NMDA receptor antagonistsNMDA receptor antagonists– Dextromethorphan/memantidine – ‘no good Dextromethorphan/memantidine – ‘no good

evidence’evidence’

NK1 receptor antagonists NK1 receptor antagonists – ‘‘no better than placebo in diabetic neuropathy’no better than placebo in diabetic neuropathy’

CannabinoidsCannabinoidsCapsican analoguesCapsican analogues

Treatment StrategiesTreatment Strategies

Best first line treatment unclearBest first line treatment unclear

Recent ‘evidence based algorithm’ TCAs Recent ‘evidence based algorithm’ TCAs then opioids then gabapentinthen opioids then gabapentin

Few head to head studies/conflicting Few head to head studies/conflicting resultsresults

Single or combination therapy?Single or combination therapy?

No treatment completely effectiveNo treatment completely effective