Diabetes

Diabetic Peripheral Neuropathy: Diagnosis and Treatment

SUMMARY:

Painful diabetic peripheral neuropathy is a common complication of diabetes that affects more than 16% of patients with diabetes during their lifetimes. Incidence increases with longer duration of diabetes and poor glycemic control. Diabetic peripheral neuropathy can lead to pain, tingling, and loss of sensation, which can increase the risk of foot ulcers and infections, and eventually result in limb amputation. Proper management and treatment of diabetic peripheral neuropathy is crucial to prevent further damage and improve the quality of life for those living with this condition. Of note, diabetes is also associated with various autonomic neuropathies, including cardiovascular, gastrointestinal, and genitourinary autonomic neuropathies

Diagnosis and Presentation

Patients with DM should be regularly assessed for the development of peripheral neuropathy
- Up to 50% of neuropathy cases are asymptomatic, possibly leading to injuries and diabetic foot ulcers if not recognized early. Preventative foot care should be implemented proactively.
- ADA recommends initial assessment at the time of DM2 diagnosis and at five years after diagnosis of DM1
- Assessment should be repeated at least annually thereafter
Diabetic peripheral neuropathy is a diagnosis of exclusion and other causes should be ruled out, such as:
- B12 deficiency
- Kidney disease
- Malignancies
- HIV/Hep C infection
- Uremic polyneuropathy
- Chronic inflammatory demyelinating neuropathy
- Inherited neuropathies
- Hypothyroidism
- Vasculitis
Risk factors for diabetic neuropathy include: Longer duration of DM | Poor glycemic control | HLD | Smoking | Obesity | HTN | Chronic alcohol use | Older age
Diabetic neuropathy is typically a polyneuropathy that is: Symmetric | Distal | Sensory
- Large fiber damage results in loss of vibration and proprioception
- Small fiber damage results in loss of temperature, pain and light touch sensation
Screening Exam should include one of the following clinical tests:
- Temperature or pinprick sensation (small-fiber function)
- Vibration sensation using a 128-Hz tuning fork (large-fiber function)
Neuropathic pain is often the presenting symptom of diabetic neuropathy and is described a burning or electric shock like pain
- Can occur with paresthesia
- Often worse as night
- Associated with hyperalgesia and allodynia (i.e., pain worsens when putting on socks)
Electrophysiological testing or referral to a neurologist is rarely needed for diagnosis
- Can be done in cases of clinical uncertainty

Treatment

Neuropathic pain can be severe and impact quality of life, including sleep and mobility, and can contribute to anxiety and depression.
American Academy of Neurology (AAN) recommends initial treatment of pain address comorbid sleep and mood disorders.
Patients should be counseled that no treatment can reverse the underlying nerve damage from neuropathy, but glycemic control can slow its progression. Complete resolution of pain is unlikely.
- Clinical trials of approved medications used a 30% pain reduction as a successful outcome
Given limited efficacy with therapy, prevention of the development and progression of diabetic neuropathy is key
- Focus on glycemic control and management of risk factors e.g., obesity, dyslipidemia, hypertension, and tobacco and alcohol use | Healthy lifestyle choices | Blood pressure control)

Pharmacologic

Dose adjustment for the level of renal function is required for many of the drugs below and must be reviewed before prescribing
Gabapentinoids
- Can cause peripheral edema, use cautiously in patients with concurrent liver, renal and/or heart disease
- Gabapentin: 900 to 3600 mg/d
- Pregabalin (Lyrica): 300 to 600 mg/d
- Mirogabalin (Tarlige): 15 to 30 mg/d
SNRIs
- GI side effects may limit use
- Duloxetine (Cymbalta): 40 to 60 mg/d
- Desvenlafaxine (Pristiq): 200mg/d
- Venlafaxine (Effexor): 150 to 225mg/d
Tricyclic antidepressant
- Anti-cholinergic effects may limit use
- Avoid in patients with difficulty with urinary retention, orthostatic hypotension
- Amitriptyline (Elavil): 75 to 150 mg/d
Sodium channel blockers
- Lamotrigine (Lamictal): 200 to 400 mg/d
- Lacosamide (Vimpat): 400mg/d
- Oxcarbazepine (Trileptal): 1,400 to 1,800 mg/d
- Valproic acid (Depakote): 1,000 to 1,200 mg/d or 20 mg/kg/d | Teratogenic | Significant adverse effects and should not be offered to any patient unless multiple other medications have failed
Topical
- Capsaicin: 8% patch for 30 min/application or 0.075% lotion 4 times per day | May have application site skin reactions
Other medications
- Nabilone, a synthetic cannabinoid, may improve pain
- Ginko biloba is possibly more likely than placebo to improve pain

Non-Pharmacologic

Cognitive behavioral therapy (CBT)
- Evidence for use of CBT for chronic pain is robust, and research is ongoing for the use of CBT for neuropathic pain
Patients who prefer non-pharmacologic methods can also be offered: Mindfulness | Tai Chi | Exercise
- Outside of patient’s personal preference, these should not be offered as first line monotherapies

Not Recommended

Opioids | Tramadol | Tapentadol
- High likelihood of severe dose-dependent long-term adverse consequences
- No clinical trial of opioids has demonstrated meaningful clinical improvement for patients.
- Patient already on opioids should be safely tapered off
- Tramadol carries the added risk of possible serotonin syndrome

Follow Up Care

Multiple pharmacologic agents may need to be tried before the patient finds a regimen that improves their pain
If one treatment fails, clinicians should trial a medication from a different class
The typical duration of treatment in which efficacy is demonstrated is approximately 12 weeks
- An intervention to improve pain should be considered a failure when it is either ineffective after 12 weeks or side effects make continued use intolerable
If only partial or inadequate pain relief with a drug in one class, a drug in a second class may be added for greater combined efficacy
When using combination therapy, consider prescribing each agent at lower doses

KEY POINTS:

Diabetic neuropathy is a common complication of diabetes that can lead to uncontrolled pain, disability, and eventual limb amputation
Prevention of diabetic neuropathy with strict glycemic control is crucial as the pain and progression of diabetic neuropathy is difficult to control once it begins
SNRIs, gabapentinoids, TCAs and sodium channel blockers all have efficacy in the treatment of diabetic neuropathy
Patients should be counseled that these medications can improve pain levels, but are unlikely to drop their pain to zero or reverse nerve damage