New Guideline on Diabetic Neuropathic Pain Rx: Is It Really New?

Three professional organizations-the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation-have issued a new, evidence-based guideline for the treatment of diabetic neuropathic pain (DNP) based on a review of literature through the middle of 2008.¹

There is no doubt that because the number of cases of diabetes is rapidly growing in this country, so is the number of patients with DNP. Thus any new recommendations for improving treatment of DNP are welcome. However, that I find little in this guideline that wasn’t already well-known. My review of the subject was published shortly before the guideline.²
 

The finding that has drawn most attention is that pregabalin (Lyrica) has the most support for the treatment of DNP based on the extent and quality of published studies. However, the guideline also found that several other medications had a high level of support. These include:
o Antidepressants (ie, amitriptyline [Elavil], duloxetine [Cymbalta], venlafaxine [Effexor], all serotonin-norepinephrine reuptake inhibitors)
o  Anticonvulsants (gabapentin [Neurontin] and sodium valproate
o Opioids (dextromethorphan, morphine, tramadol [Ultram], and oxycodone)
o Capsaicin (Zostrix)
o Isosorbide dinitrate spray, a vasodilator.

Of the non-pharmacologic therapies, the guideline also found this level of support for percutaneous electrical stimulation. A lower level of support was found for lidocaine patch (Lidoderm).

The only finding at all surprising is the high level of support for isosorbide dinitrate spray. I have never used this for DNP nor can I recall any colleagues prescribing it, but I certainly will consider it for future use.

Based on available evidence, the guideline could not determine the efficacy of several other treatments, including the antidepressants desipramine, imipramine, and fluoxetine, and the anticonvulsant topiramate.

There was also insufficient evidence to base a decision about exercise and acupuncture. More discussion about acupuncture would have been helpful. The guideline found strong evidence to support percutaneous electrical nerve stimulation (PENS) but failed to note that most physician acupuncturists in the US use electrical stimulation to stimulate the acupuncture needles and therefore the acupuncture points, and that this is very similar (if not identical) to PENS.

The guideline also recommended against use of a number of treatments. These include:
o Anticonvulsants (oxcarbazepine [Trileptal], lamotrigine, [Lamictal], and lacosamide [Vimpat]
o Clonidine (Catapres)
o Mexiletine (Mexitil)
o Pentoxifylline (Trental)

Similarly it found no support for the use magnetic field treatment; low-intensity laser therapy; or Reiki therapy, based on energy transfer from practitioner to patient.

It might appear that the guideline found pregabalin to be the most effective treatment for DNP. However, Mitka, the lead author, noted in an interview in JAMA³ that its effectiveness was supported by more rigorous research than for other agents and that the guideline sought to give evidence for what clinicians are doing-not to recommend an order of treatment (page 2507). I believe this clarification is important. 

Because of its focus on efficacy, the guideline largely excludes other factors that might play a major role in deciding a treatment algorithm. For example, if the pain is relatively localized I usually recommend starting with a lidocaine patch. It is essentially free of systemic side-effects, does not interact with other medications, is easy to use, and can provide significant pain relief for DNP. Although capsaicin-which the guideline found to have a higher level of support-has many similar properties, it is often less well tolerated than the lidocaine patch.

The guideline expresses concerns about use of sodium valproate, despite its efficacy for DNP. This agent is potentially teratogenic and should be avoided in women with diabetes who may become pregnant.

The guideline also did not take into account comorbid disorders. Depression frequently coexists with both chronic pain and diabetes and if clinical depression is present along with the DNP, it makes sense to initiate treatment with an antidepressant. Also, a real world element is cost. If a patient with DNP can tolerate amitriptyline-and I believe an antidepressant is indicated- I would consider using this agent first because it is available in generic form.

Perhaps what is most important about the guideline is not what it found, but what it did not find. It noted the lack of studies that lasted longer than 20 weeks-a short time considering that DNP is usually a chronic condition. Thus there is little information on the long-term benefits of any of the treatments.
Few of the studies that the authors of the guideline evaluated explored anything other than level of pain. Yet when we treat chronic pain, the most important goals are usually the improvement of activity level and quality of life and not the pain alone.

Finally, what I consider to be the most important limitation in the studies that were identified by the guideline is that few reported head-to-head studies between the treatments. We have virtually no studies that compare the 3 major drug groups the guideline found most supported by the literature: antidepressants, anticonvulsants, and opioids. These groups appear to exert their analgesic effects by different mechanisms. The obvious questions that still remain unanswered are why some patients with DNP respond to drugs in one class but not to those in the others-and why there may be different responses to various drugs within each class.

Without guidance about which medication is most likely to be effective for any patient, choosing initial therapy is primarily guesswork. Clearer insights into the cause of DNP-and whether it might be multiple disorders rather than a single entity-are also needed.

References
1. Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Neurology. 2011:76:1758-1765. http://www.neurology.org/content/early/2011/04/08/WNL.0b013e3182166ebe
2. King SA. Diabetic peripheral neuropathic pain: effective management. Consultant. 2011:41:197-200. http://www.consultantlive.com/pain/content/article/10162/1836722
3. Mitka M. Group releases new guideline on options for treating painful diabetic neuropathy. JAMA. 2011;305:2507-2508.