Diabetic Neuropathy

• Overall prevalence of diabetic neuropathy is 10-20%
• The majority of patients have features of a chronic, sensorimotor, peripheral neuropathy

• Duration of diabetes; from 10% at diagnosis up to 53% by 25yrs post-diagnosis
• The degree of glycaemic control; both absolute HbA_1c level and change in level
• Hypertension
• Smoking
• Dyslipidaemia
• High BMI

• The epidemiology of painful diabetic neuropathy is not widely studied
• It is estimated that 50% of those with diabetic neuropathy experience pain
• A UK-based study found 1 in 3 diabetic patients have pain
• Up to 25% of patients have pain without neuropathy
• The prevalence of painful neuropathy is twice as high in T2DM compared to T1DM
• Risk factors for development of painful neuropathy largely overlap with those for diabetic neuropathy

• Chronic sensorimotor polyneuropathy affecting C-fibres, Aδ and Aβ fibres and mixed nerves
• Acute, painful sensory neuropathy
• Autonomic neuropathy

• Mononeuropathies affecting either peripheral or cranial nerves
• Mononeuritis mulitplex
• Focal limb or trunk involvement e.g. cervical neuropathy
• Compression neuropathy e.g. carpal tunnel syndrome
• Inflammatory demyelinating polyneuropathies

• Diabetic neuropathy occurs following a complex interaction between:
• Hyperglycaemia-induced metabolic and biochemical changes
• Inadequate perfusion from micro-vascular changes
• Both serve to increase oxidative stress
• Oxidative stress itself causes ROS production, endothelial damage and imbalance of factors controlling microvascular tone (endothelin vs. nitric oxide)
• These pathological changes cause neuronal ischaemia and impaired regeneration

• Activation of the polyol pathway, disrupting neuronal structure and depleting neuronal energy
• Advanced glycation end products, with glycosylation of amino acid groups impairing neuronal and vascular structure/function
• Cytokine-induction by advanced glycation end-products
• Poly-ADP-ribose polymerase, a DNA repair enzyme that is overactive in hyperglycaemia, depleting energy and causing cell death
• Impaired neurotrophic support owing to reduced levels of insulin, nerve growth factor and neurotrophin
• Abnormal long-chain fatty acid and prostaglandin metabolism, altering neuronal and microvascular structure
• Increased production of protein kinase C from diacylglycerol

• These generally depend on the type of nerve fibre involved


• Sensory symptoms
• Include paraesthesia, pain or numbness
• Typically symmetrical in a 'stocking' distribution


• Motor symptoms
• Difficulty mobilising
• Difficult handling small objects
• Wasting of the intrinsic muscles of the hands or feet


• Examination findings include:
• Impaired proprioception and vibration sense
• Depressed reflexes
• Unsteady gaits
• Wasting of the intrinsic muscles of the hands or feet

• Up to 25% of patients suffer pain without evidence of neuropathy
• Pain is typically:
• Moderate-severe intensity
• Worse at night
• Affects both feet
• Difficult to characterise, but often neuropathic: burning | electric-shock | shooting/stabbing | pins & needles | numbness
• Associated with features of neuropathic pain such as allodynia and hyperalgesia

• Management is challenging, but should follow an MDT and biopsychosocial approach

• The best way of reducing the risk of developing painful neuropathy is through better glycaemic control
• In patients with established pain, avoiding large fluctuations in glucose levels is important as these are associated with greater pain intensity
• Rapid over-correction of blood sugar may itself cause pain, so should be avoided

• Smoking cessation
• Weight loss
• Treatment of underlying comorbidities e.g. hypertension, hyperlipidaemia

• Duloxetine (SNRI) is the first-line drug in painful diabetic neuropathy
• Started at 30-60mg OD
• Up-titrated to a maximum daily dose of 120mg (i.e. 60mg BD)
• NNT for a dose of 60-120mg is approximately 6


• Amitriptyline is recommended as first-line if duloxetine is contra-indicated
• Started at 10mg ON and up-titrated by 10mg/week to a maximum daily dose of 150mg
• The NNT is ∽3, but it has a high number needed to harm (6) and number for major adverse events (28)
• Frequently causes anti-cholinergic side-effects which lead to patient intolerance


• Venlafaxine is another SNRI; it has moderate efficacy but its use is hindered by cardiac side-effects

• Pregabalin is the recommended second-line agent for painful neuropathy
• Started at 150mg daily (e.g. 75mg BD or 50mg TDS)
• Can be up-titrated to a maximum daily dose of 600mg


• Gabapentin is an alternative
• Starting dose 300mg daily
• Up-titrated to maximum daily dose of 1200mg


• At their maximum doses, both have an NNT of 5-7 and a NNH of 6-7

• Conventional opioids e.g. morphine, oxycodone may have moderate efficacy
• However, they suffer from:
• High potential for abuse
• Adverse long-term endocrine and immunological effects
• Adverse short-term effects as maximum effectiveness comes from doses of 180mg MME


• Tramadol may be a better choice owing to its weak SNRI effect and low abuse potential
• It is started at 50mg daily
• May be up-titrated to a maximum daily dose of 400mg
• Tapentadol is an alternative, but has a higher NNT for neuropathic pain

• Capsaicin 0.075% cream applied 3-4x/daily may be effective, with an NNT of 6-7
• The 8% patch may provide more sustained efficacy


• Lidocaine 5% patches


• Nitrate topical spray or patch
• May work via generation of nitric oxide and improved microvascular perfusion

• Some treatments target the natural history of diabetic neuropathy
• Alpha-lipoic acid is an antioxidant which can improve neuropathy and reduce pain scores
• Other potential treatments include:
• Aldose reductase inhibitors
• Protein kinase C inhibitors
• Inhibitors of glycation

• There is a paucity of evidence to support the routine use of methods such as TENS, acupuncture, phototherapy or spinal cord stimulation