Primary Care Corner with Geoffrey Modest MD: Diabetic Neuropathy Guidelines

By Dr. Geoffrey Modest

The American Diabetes Association just came out with their position paper on diabetic neuropathy (see DOI: 10.2337/dc16-2042). I will limit my points to type 2 diabetes, though type 1 is covered in this paper

Summary of points:

• Diabetic neuropathy is a diagnosis of exclusion: diabetic patients may well have non-diabetic causes of neuropathy that should be pursued.
• 50% of diabetic neuropathies are asymptomatic. It is important to assess for them, for example, to decrease the likelihood of significant foot trauma, improve symptoms and quality of life, and decrease sequelae
• Prevention of neuropathy:
  • Data are largely for distal symmetric polyneuropathy (DSPN) and for cardiovascular autonomic neuropathy (CAN).
  • Best evidence is for those with type I diabetes where it is important to optimize glucose control as early as possible: 78% relative risk reduction with enhanced diabetes control
  • Risk reduction seems to be less in glucose control with type 2 diabetes, perhaps in part reflecting the different pathophysiology and comorbidities: type 2 diabetes tends to be associated more with overweight, polypharmacy, older age; but also many patients with type 2 diabetes have been prediabetic or diabetic for many years prior to diagnosis. In fact 10-15% of newly diagnosed diabetes already have evidence of DSPN.
• Distal symmetric polyneuropathy (DSPN)
  • Most common (75% of all neuropathies). Defined clinically by symptoms or signs. Electrophysiologic testing or neurology referral are rarely needed.
  • 50% of people have DSPN after 10 years of disease, and is associated with levels of glycemia, height (perhaps as a proxy of nerve length), smoking, blood pressure, weight, and lipids
  • Those with predominantly small-fiber neuropathy present with pain, burning or tingling feeling, sometimes with a shooting sensation. There may also be hyperalgesia. And this may be found in 10 to 30% of patients just with impaired glucose tolerance. Those with large fiber involvement have numbness, tingling without pain, and loss of protective sensation
  • DSPN is associated with foot ulceration/amputation risk (important to assess regularly and refer to podiatry early), Charcot neuro-arthropathy, unsteadiness and falls (should assess gait/balance, though minimal data to support), and quality of life (DSPN can really affect quality of life, and is associated with depression, anxiety, medication nonadherence)
  • Patient should be assessed annually, those with type I diabetes should be assessed starting 5 years after the diagnosis. Consider assessing those with glucose intolerance as well. Assessment should include temperature or pinprick sensation (small fiber function), vibration sense with a 128 Hz tuning fork, proprioception, ankle reflexes, and 10-g monofilament (large fiber function), and the 10 g monofilament also helps assess risk for ulceration and amputation
  • Important to rule out the myriad of other causes of neuropathy, including vitamin B12 (see blog https://stg-blogs.bmj.com/bmjebmspotlight/2017/02/23/primary-care-corner-with-geoffrey-modest-md-vitamin-b12-and-diabetic-autonomic-neuropathy/ which notes the overall increased incidence of B12 deficiency in diabetics) as well as infections (HIV, hepatitis B, Lyme), thyroid disease, paraproteinemia, alcohol or medications, heavy metal poisoning/work-related exposures, etc.
  • Symptom management: consider pregabalin or duloxetine as the initial​ approach. Though gabapentin may also be used (they do comment that pregabalin has a more linear, dose-proportional absorption and more rapid onset of action). They also note that tricylcic antidepressants (TCAs) are effective but beware of adverse effects. There seems to be some efficacy for the selective norepinephrine/serotonin reuptake inhibitor venlafaxine (dose 150-225 mg/d), mechanistically similar to duloxetine. Opioids should be avoided, given the risks of addiction, as either first- or second-line agents. However, tapentadolextended release, which has analgesic effects both through the m-receptor and noraderenaline reuptake inhibition, is FDA-approved, though there are systematic reviews/ meta-analyses which challenge its effectiveness. And some patients do seem to respond to adding low doses of these opioids in combo with the above agents).
• Autonomic Neuropathies
  • Cardiovascular autonomic neuropathy (CAN)
    • May be present prior to a formal diagnosis of diabetes, ​is found in up to 60% of patients after 15 years, and is an independent risk factor for cardiovascular mortality (2+ fold increased risk, controlling for other risk factors), arrhythmia, silent ischemia, any major cardiovascular event, and myocardial dysfunction.
    • May be asymptomatic early and detected only by decreased heart rate variability with deep breathing, esp with EKG monitoring (see https://stg-blogs.bmj.com/bmjebmspotlight/2017/02/23/primary-care-corner-with-geoffrey-modest-md-vitamin-b12-and-diabetic-autonomic-neuropathy/ which discusses ways to measure CAN), but can include symptoms of light-headedness, weakness, palpitations, fainting/syncope. Exam may show resting tachycardia, or orthostatic hypotension without compensatory increase in pulse.
    • Symptom management:
      • Optimize glucose control (to prevent or delay CAN, though this is most evident in type 1 diabetes, but some benefit in studies with type 2), reinforcing lifestyle interventions both in prediabetics and diabetics prior to developing CAN. For those with orthostatic hypotension, can use both nonpharmacologic treatments (exercise, assuring adequate fluid intake/volume repletion) and meds (fludrocortisone, midodrine)
    • Gastrointestinal neuropathies can be anywhere in GI tract, from esophageal dysmotility to gastroparesis to lower GI symptomsof diarrhea, constipation, incontinence
      • Gastroparesis
        • ​May be present in 1% of type 2 diabetics, from a community-based study (higher in type 1 diabetes). Can affect glucose variability and unexplained hypoglycemia because of changes in food absorption. [my experience suggests that gastroparesis may well be more common than this]
        • ​Consider checking for symptoms in those with other microvascular complications  (“C” recommendation), exclude other causes (g. opiates, GLP-1 agonists (grade “C” recommendation”) [and, I would add, considering decreasing dose of metformin, esp since 500mg once a day or even 250mg seems to add substantial clinical benefit], and can do gastric emptying studies to document (grade “B” recommendation”) [I would also add that gastroparesis is usually evident by history, and that it is probably useful just to try the nonpharmacologic and even pharmacologic therapies empirically]
        • Treatment includes eating multiple small meals/d, decreasing dietary fat (which also causes gastroparesis), decreasing other drugs than those mentioned above which can make it worse (g. anticholinergics, pramlintide and ? DPP-4 inhibitors), and one can prescribe metoclopramide, the only FDA-approved agent, though it is associated with extrapyramidal symptoms, acute dystonic reactions, akathisia, tardive dyskinesia, acute dystonic reactions) and is recommended to use for only 5 days (which is problematic for such a chronic condition, and I have patients on this agent for much longer, with frequent assessments by me for the above adverse reactions)
      • Urogenital neuropathies includes bladder and sexual dysfunction, the latter including erectile dysfunction (3x more common in diabetics, may involve combo of autonomic neuropathy, vascular disease, and I would add psych issues, such as depression, stress, etc.) and/or retrograde ejaculation in men and sexual dysfunction in women (decreased sexual desire, increased pain with intercourse, decreased sexual arousal, inadequate lubrication).
        • Bladder dysfunction should be assessed in those with recurrent urinary tract infections, pyelonephritis, incontinence, palpable bladder
        • Recommendations: consider screening men with other forms of neuropathy for ED (grade C) and women with other forms of neuropathy for lower urinary tract symptoms and sexual dysfunction (grade E)
      • ​Sudomotor dysfunction includes dry skin, anhidrosis, or heat intolerance, and occasionally gustatory sweating (food consumption, and occasionally just the smell of food, leading to sweating of head and neck area)
      • Other neuropathies:
        • Mononeuropathies: especially of median, ulnar, radial and common peroneal nerves. cranial neuropathies are rare but include cranial nerves III, IV, VI, VII and usually resolve spontaneously over months
        • Diabetic radiculoplexus neuropathy (also called diabetic amyotrophy): unilateral thigh pain, weight loss, followed by motor weakness. self-limited (though I have a type 1 diabetic patient with this in one of his shoulders)

Commentary:

• They do promote pregabalinand duloxetine as their primary go-to’s. I personally do not use them till much later in the pyramid of meds, partly because they are relatively new agents (and the older ones have stood the test of time), partly because there are mechanistically similar drugs available (gabapentin and venlafaxine), partly because these are non-generic and quite expensive, and partly (e., a lot) because they require prior approvals from many insurers.​
• In the vast majority of cases, I have prescribed tricyclic antidepressants with great success. Although amitriptyline is the one used the most overall, it has the most adverse effects. I prescribe either desipramine or nortriptyline, which work as well and with many fewer adverse effects (desipramine has the fewest, but nortriptyline is helpful to take at night if the patient has trouble sleeping). The usually effective doses are desipramine 25-50mg (occasionally 75), or nortriptyline 10-50mg. Not sure why, but the 2012 ADA guidelines (see Diabetes Care 35:2451–2458, 2012) found that there was no significant difference between amitriptyline, duloxetine and pregabalin, though the current guidelines seems to have booted TCAs off the top tier (they are generic with long history of use and knowledge of long-term adverse effects, both plusses, which does raise the question to me of adverse drug-company induced bias….)
• Gabapentin is used a lot for neuropathy, though the studies have been mixed (and the drug company has been taken to task for withholding large, unpublished negative studies).  And in my limited experience, is associated with many adverse effects and requires a very slow titration up.

So, a pretty useful compilation of diabetic neuropathies, along with reasonable approaches (though there are no medications which actually treat the neuropathies, only ameliorate the symptoms). My own approach is that anyone with any mono or polyneuropathy should be checked for diabetes (for example, they limit the cranial nerve neuropathies to the facial and extraocular movement nerves, though I have seen a couple of diabetic patients with anosmia.) Also, they do not comment that it is not so uncommon in diabetics to have radiculopathies typically on the trunk which simulating zoster clinically and respond to the above meds.

See https://stg-blogs.bmj.com/bmjebmspotlight/2015/01/29/primary-care-corner-with-geoffrey-modest-md-meds-for-diabetic-neuropathy/ for a meta-analysis of the meds used for DSPN, finding that SNRIs, capsaicin, tricyclics and anticonvulsants work for short-term pain control (seemed that SNRIs and TCAs were best). Opiates were last by a fair margin.