What Works for Painful Diabetic Neuropathy?

Abstract & Commentary

By Joseph E. Scherger, MD, MPH, Clinical Professor, University of California, San Diego, CA. Dr. Scherger reports no financial relationships relevant to this field of study.

Synopsis: A systematic review covering 48 years gives pregabalin (Lyrica) Level A evidence for the treatment of diabetic neuropathy. Gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine may be as effective but only receive a Level B recommendation based on the quality of the studies.

Source: Bril V, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Neurology 2011;76:1758-1765.

A group representing the american academy of neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation conducted a systematic review of the literature from 1960 to 2008 on studies of therapies for the treatment of painful diabetic neuropathy (PDN). The research question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with painful diabetic neuropathy?" The search identified 2234 citations: 463 were considered potentially relevant and 79 articles were selected for the systematic review.

All studies found that pregabalin relieved pain, but the effect was small relative to placebo, reducing pain by 11%-13% on the 11-point Likert scale in the Class I studies. Other studies showed modest effectiveness for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine. Pain relievers such as dextromethorphan, morphine sulfate, tramadol, and oxycodone also have evidence of effectiveness. Electrical stimulation, topical capsaicin, and isosorbide dinitrate spray were also effective. Treatments not recommended were oxcarbazepine, lamotrigine, lacosamide, clonidine, pentoxifylline, mexiletine, magnetic field treatment, low-intensity laser therapy, and Reiki therapy.

Recommendations from the study group for anticonvulsants were:

1. If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).

2. Gabapentin and sodium valproate should be considered for the treatment of PDN (Level B).

3. There is insufficient evidence to support or refute the use of topiramate for the treatment of PDN (Level U).

4. Oxcarbazepine, lamotrigine, and lacosamide should probably not be considered for the treatment of PDN (Level B).

Recommendations for antidepressants were:

1. Amitriptyline, venlafaxine, and duloxetine should be considered for the treatment of PDN (Level B). Data were insufficient to recommend one of these agents over the others.

2. Venlafaxine may be added to gabapentin for a better response (Level C).

3. There is insufficient evidence to support or refute the use of desipramine, imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine in the treatment of PDN (Level U).

Recommendations for other therapies were:

1. Capsaicin and isosorbide dinitrate spray should be considered for the treatment of PDN (Level B).

2. Clonidine, pentoxifylline, and mexiletine should probably not be considered for the treatment of PDN (Level B).

3. The lidoderm patch may be considered for the treatment of PDN (Level C).

4. There is insufficient evidence to support or refute the usefulness of vitamins and alpha-lipoic acid in the treatment of PDN (Level U).

Commentary

There is still no magic bullet for treating PDN. Even with the neuropathic pain anticonvulsant pregabalin receiving a Level A recommendation in this systematic review, the effect was modest. The authors of this report were quick to point out that pregabalin may not be superior to other drugs, such as the much less expensive gabapentin, but pregabalin benefitted from superior research studies.

I've been using amitriptyline for PDN for most of my 30-plus year career with some effectiveness. It is good to see that it stands up to Level B evidence. Since PDN is a long-term problem, effective inexpensive therapies are important. I see this systematic review confirming that.

I congratulate the neurology organizations for conducting this robust review of so many therapies. Because of this, we in primary care will not be shooting in the dark as much or making unnecessary referrals for this common and often frustrating condition.