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Overview
• Affirmation
• Neuropathy Diagnosis• Review of common causes of neuropathy• Review of small fiber neuropathy• Diagnostic tools and practice parameter recommendations
• Treatment of neuropathic pain• Conventional medications• New medications• Cannabinoids
Methods
• Medline database search 2000-2016 (keywords:
neuropathy, peripheral neuropathy, small fiber neuropathy, idiopathic neuropathy, neuropathic pain, pain, impaired fasting glucose, impaired glucose tolerance, diabetic neuropathy, cannabidiol, cannabinoids)
• Review of relevant earlier publications
• Exclusion of more straightforward or less common neuropathies (chemotherapy neuropathy, CIDP, Guillain-Barre, others)
Some anatomy of the peripheral nerves
• Small fiber = • A-delta and C-fiber• Thinly myelinated and unmyelinated nerves• Temperature, pain, light touch• Autonomic function
• Large fiber = • A-alpha and A-beta• Large diameter, myelinated nerves• Proprioception, vibration, light touch, motor (alpha
motorneurons)
Periquet: Neurology, Volume 53(8).November 10, 1999.1641-1647
Small fiber neuropathy
Symptoms:
• Feet pain• Burning
• Tingling
• Aching
• Electrical
• Stabbing
• Numbness
• Sweat or color changes in feet
Exam findings:
• Gradient to pain, light touch sensation
• Normal vibration and proprioception
• Normal strength and deep tendon reflexes
Large Fiber Neuropathy
Symptoms:
• Weakness
• Gait instability
Exam Findings:
• Distal Weakness
• Distal atrophy
• Distal loss of DTRs
• Impaired proprioception and vibration
The etiology of a large fiber neuropathy is easier to find
• There are objective findings on physical exam
• Blood testing is higher yield
• Can be detected and characterized on EMG/NCS
Small fiber neuropathy is more likely to be idiopathic
• Symptoms may be vague or may resemble vascular disease or mechanical foot issues
• Few if any objective findings on physical exam
• Blood testing and EMG/NCS are often normal
Large fiber
• B12• GBS• CIDP• ALS• Hereditary
Small fiber
• Impaired glucose metabolism
• Autoimmune• RA, SLE, Sjogren’s
• Toxic• Deficiencies
• Thyroid• B12• Folate
• Idiopathic
Large and/or small fiber
• DM
• Chemotherapy
• Paraproteinemia
• HIV
• Autoimmune (vasculitic, celiac)
• Diagnostic yield of lab testing is 9-58% in all cases of neuropathy.
• Diagnostic yield falls to 10% in patients with normal EMG and NCS (small fiber neuropathy).
• Most idiopathic neuropathies are predominantly small-fiber neuropathies.
Many neuropathy cases are idiopathic
• 2016 study of 369 patients with “idiopathic neuropathy”:
• 32.7% idiopathic
• 25% impaired glucose metabolism
• 20% CIDP
• 7% MGUS
Muscle Nerve 2016;53:856-861
Glucose testing per ADA:Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160-3167
Fasting glucose
• Impaired: 100-125
• Diabetic: 126 or greater
A1C: DM 6.5 or greater
2 hr glucose tolerance
• Impaired: 140-200
• Diabetic: 200 or greater
• Using only HgbA1C >6.5 misses 49% of patients with OGTT >200
• Fasting glucose more sensitive than A1C
• 2hrOGTT more sensitive than fasting glucose
40 patients with IGM and neuropathy
• Lifestyle intervention:• 7% weight reduction• Increased exercise to 150 min/week
• Measured metabolic and neurologic parameters at baseline and at 1 year.
• Significant improvement in:• BMI, OGTT, Total cholesterol• Skin biopsies, QSART, sural amplitude• Neuropathic pain
AG Smith: Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 2006; 29:1294-2199.
Vascular risk factors may be neuropathy risk factors….
Prospective trial of idiopathic neuropathy
• 50 patients with IPN• 32% had abnormal FPG or OGTT
• 50 controls• 14% had abnormal FPG or OGTT
• Glucose status not significant (P=0.45)• Significant relationships:
• Hypertriglyceridemia• Hyperinsulinemia
Hughes RAC. A controlled investigation of the cause of chronic axonal idiopathic polyneuropathy. Brain, 2004: 127;1723-1730.
Prospective study of 1172 patients with DM
• Endpoint: development of neuropathy at eight year follow-up.
• 276 developed neuropathy (23.5%)
• Incidence of neuropathy related to:
• Duration of DM
• HgbA1C value
Tesfaye S. NEJM 2005;352:341-50
NEJM 2005, cont.
• Risk factors for developing neuropathy, after adjusting for HgbA1C and duration of diabetes:• Total cholesterol
• LDL
• Triglycerides
• BMI
• Albuminuria
• Retinopathy
• Cardiovascular disease
• Smoking
• (P Values .03 – 0.001)
Cross sectional study of 219 patients with IPN• Assessed IPN patients for prevalence of metabolic syndrome
• Controls: 175 diabetic patients without neuropathy
• Compared to diabetics without neuropathy, normoglycemicneuropathy patients had significantly:• Higher total cholesterol• Higher LDL• Higher TG• Lower HDL
Smith AG. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci 2008; 273(1-2):25-28.
Other papers linking neuropathy to vascular risk factors:
• Improvement in NCS with trandolapril• Lancet 1998;352:1978-1981
• Improvement in NCS with atorvastatin• Minerva Endocrinol 2012;37:195-200
• Inverse correlation between small fiber function and TG levels• Muscle Nerve 2015;52:113-119
• Fibrate and statin use negatively associated with development of neuropathy at 5 years• TM Davis. Lipid-lowering therapy protects against peripheral sensory neuropathy
in Type 2 Diabetes. 2007: Abstract number 0004-OR
“These findings demonstrate an association between neuropathy and metabolic syndrome features other than hyperglycemia.”
• Smith AG. J Neurol Sci 2008; 273(1-2):25-28
2009 consensus recommendations for laboratory testing of neuropathy
• American Academy of Neurology
• American Academy of Electrodiagnostic and Neuromuscular Medicine
2009 consensus recommendations for laboratory testing of neuropathy
• CBC,
• ESR
• Creatinine
• LFTs
• Thyroid function
• B12
• SPEP with immunofixation
• Glucose testing
Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle and Nerve 2009: 39;116-125.
Tests not included:
• RPR
• HIV
• Heavy metals
• Folate
• Lyme
Other testing for neuropathy
• EMG/NCS
• Epidermal nerve biopsies
• Others:
• Quantitative Sudomotor Axon Reflex Test (QSART)
• Quantitative Sensory Testing (QST)
Nerve Conduction Studies
• Test large fiber sensory and motor function separately
• Do not test small fiber function
• Basic parameters:
• Conduction velocity (myelin)
• Latency (myelin)
• Amplitude size (axons)
NCS advantages
• Well-defined normal values
• Sensitive in large-fiber dysfunction
• Can identify other peripheral causes of symptoms (CIDP)
• Safe
• Establishes values for future comparison
• Also captures entrapment neuropathies
NCS limitations
• Operator dependent
• Limb temperature dependent
• Some normal values vary with patient age
• Insensitive in radiculopathy
• Tests only the peripheral nerves
• Tests only large-fiber function
Epidermal nerve biopsy
• 3mm biopsy of dermis and epidermis from ankle and thigh
• Manual or computer-aided counting of C fibers
• Sensitivity ~70-80%
• Safe. Performed in the office in <20 minutes
• Does usually not provide an etiology
Summary: Neuropathy workup
• CBC, ESR, creatinine, LFTs, thyroid function, SPEP with IFE
• A1C, FPG, 2hrOGTT
• Consider NCS, epidermal nerve biopsies
Treatment of neuropathic pain
• Conventional medications• Tricyclic antidepressants
• Serontonin-norepinephrine reuptake inhibitors
• Antiepileptics
• Narcotics
• Vitamin supplements, new medications, and other methods
• Cannabis
Tricyclic Antidepressants
• Level A evidence for efficacy• Number needed to treat: 2.1• Start at 10-25mg QHS and titrate• Nortriptyline has fewer anticholinergic side
effects than other TCAs.• Slightly increased risk of sudden cardiac death in
doses >100mg QD• Risk of serotonin syndrome
WA Ray. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharm and Therapeutics 2004;75:234-241.
Antiepileptics:Gabapentin and pregabalin
• Level A evidence
• NNT 3.9
• Dosing:
• Gabapentin 1200-3600mg QD
• Pregabalin 150-600mg QD
• Gabapentin: 100% renally cleared
• Pregabalin: Mostly renally cleared
Antidepressants: Duloxetine
• Level A evidence for efficacy
• NNT 5.2
• Dosing 30-60 QD
• Modest efficacy: considered second-line
Antidepressants:Venlafaxine
• Level A evidence for efficacy
• NNT 4.6
• Dosing 150-225mg QD.
• Modest efficacy
• Synergy with gabapentin
Other antiepileptics
• Oxcarbazepine• Equivocal evidence of efficacy in IPN
• Carbamazepine• Equivocal evidence of efficacy• Poor quality evidence
• Valproate: Studies disagree• Lamotrigine: • Questionable effect in neuropathy• Effective in TGN
• Topiramate, levetiracetam• Ineffective
Narcotics:Oxycodone and tramadol
• Level A evidence
• NNT 2.6 (oxycodone), 3.4 (tramadol)
• Dosing:• Oxycodone 10-99mg QD
• Tramadol 200-400mg QD
• Tramadol• Less addictive potential
• May reduce seizure threshold in epileptics
• Risk of serotonin syndrome
Alpha lipoic acid
• Two randomized, placebo-controlled trials demonstrate efficacy in diabetic neuropathic pain:• ALA 600mg IV QD, 5 days per week for 14 weeks.• ALA 600 or 1200mg orally for 5 weeks.
• Side effect: nausea
SYDNEY trial authors: The sensory symptoms of diabetic polyneuropathy are improved with alpha lipoic acid. Diabetes Care 2003;26:770-776.
D Ziegler: Oral treatment with alpha lipoic acid improves symptomatic diabetic polyneuropathy. Diabetes Care 2006;29:2365-2370.
Acetyl-L-carnitine
• Several studies in diabetics demonstrate at 6-12 mos improved:• Pain
• NCS values
• Sural biopsies
• Dosing: 500-1000mg TID
• Side effects: • Paresthesias
• GI
Others
• Capsaicin• Cochrane review 2009:
• Effective
• NNT about 9
• Poor studies
• EMLA cream (lidocaine/prilocaine)
Newer Neuropathic Pain Medications
• Tapentadol
• Topical clonidine
• Cannabinoids
Tapentadol
• FDA approved for painful diabetic neuropathy in 2012
• Schedule II controlled substance
• Opioid mu-receptor agonist
• Norepinephrine reuptake inhibitor
• 25-250mg BID in ER formulation
Tapentadol
• NNT for 30% pain reduction: 8.77
• “Moderate effect” according to AAN guidelines
Tapentadol in neuropathic pain:• Vinik, et al. Diabetes Care 2014;37:2302-9
• Schwartz, et al. Curr Med Res Opin 2011;27:151-162
• Schwartz, et al. Clin Drug Investig 2015;35:95-108
• Baron, et al. Pain Practice 2015;15:471-486
Topical clonidine
• 0.1% applied TID
• Not effective in severely denervated feet
Campbell, et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 2012;153:1815-1823
Cannabinoids data review
“Oregon is Celebrating Marijuana Legalization with Free Weed,” Time, 6/29/15
Cannabinoids for pain: A review of the data • Cannabis contains 60+ cannabinoids
• Focus on tetrahydrocanabinol (THC) and cannabidiol (CBD)
• THC acts on CB1 (CNS, PNS) and CB2 (immune cells) receptors
• CBD is an agonist of glycine receptors in the spinal cord, and serotinin receptors
THC and CBD improve pain
• RPCT of 48 patients with brachial plexopathy (Sativex/Nabiximols CBD:THC oral spray)
• RPCT of 16 patients with chemo neuropathy (Sativex)
• Open label study of 380 patients with diabetic neuropathy (Sativex)
• RPCT 21 patients with post-traumatic neuropathic pain (smoked)
• RPCT of 38 patients with central or peripheral neuropathic pain (smoked)
• RPCT of 125 patients with unilateral neuropathic pain (Sativex)
• RPCT of 39 patients with peripheral or central neuropathic pain (vaporized THC)
• RPCT of 246 patients with peripheral neuropathic pain (Sativex)
• RPCT of 50 patients with HIV neuropathy (smoked)
• Animal studies of CBD in chemotherapy neuropathic pain
Side effects
• Sedation, confusion, dizziness, disorientation, fatigue
• Probably mainly due to THC
• Limit utility for people who work and drive
A New Hope:Cannabidiol (CBD)
• Negative modulator of CB1 receptors
• Minimal to no psychoactivity
• FMRI shows opposite effects for CBD and THC in the basal ganglia, hippocampus, amygdala, temporal and occipital cortex
• Interacts with glycine receptors in dorsal horns and serotonin receptors
CBD
• Wide dosing range in humans without side effects (15-600mg)
• Typical dose about 10mg QD (Sativex dose 2.5mg)
• Half life about 24 hours
• Inhibits hepatic metabolization of P450 metabolized drugs
CBD studies:
• Anticonvulsant
• MS spasticity
• Parkinson’s disease
• Addiction, anxiety, psychosis
• Graft versus host
• Anti-neoplastic
• Inflammation
• ???? Neuropathic pain
Cannabis bottom line:
• THC/CBD combination is effective in improving neuropathic pain but usually with side effects.
• CBD shows promise as a neuropathic pain control cannabinoid without side effects, but studies of CBD, alone, are lacking.
Summary recommendations for neuropathic pain
• First line:• TCA, gabapentin, pregabalin
• Second line:• Venlafaxine, duloxetine• (Carbamazepine)• Oxycodone, tramadol, tapentadol
• Consider:• Oxcarbazepine, carbamazepine• Topicals• Cannabidiol
Useful summaries of neuropathic pain management:
• N Attal. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13:1153-1169
• RH Dworkin. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007:132;237-251
• Bril V. Evidence-based guideline: treatment of painful diabetic neuropath. Report of the AAN, AANEM, and the AAPMR. Neurology 2011;76:1758-65
Summary: an anecdotal approach to neuropathy
• Establish neuropathy symptoms
• Look for length-dependency on exam
• Fasting glucose, 2hrOGTT, A1C, TSH, MMA, SPEP, UPEP, ANA, RF, ssA, ssB
• Other workup especially if idiopathic, severe, asymmetric, diffuse
• Gabapentin, nortriptyline, Lyrica, CBZ
• Cymbalta, EMLA CBD
