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5 Articles in this Series
Introduction
2018 IASP World Congress on Pain: A Preview
Informal Social Support for Pain: Moving the Research Forward
Spinal Cord Stimulation Evidence: What's Available and What's Needed
Symptomatic Treatment of Painful Diabetic Neuropathy
Translating Trials into Practice from a Primary Care Perspective

Symptomatic Treatment of Painful Diabetic Neuropathy

A review by Troels S. Jensen, MD, DMSC, of the current evidence for DN and PDN treatment leaves promising, but otherwise underwhelming results. A 2018 IASP World Congress on Pain highlight.

Neuropathy is a major complication of diabetes, and approximately 20% of patients with diabetes will have painful diabetic neuropathy (PDN). However, despite its high prevalence, it still remains largely misunderstood. For example, it is still unclear why only half of patients will develop neuropathy, and why it is painful in only some patients. The clinical aspect of PDN is heterogeneous, and both painful and non-painful diabetic neuropathies both present themselves with many different variables.

Troels S. Jensen MD, DMSC, professor of neurology at the Aarhus University Hospital in Denmark, presented “Symptomatic Treatment of Pain Diabetic Neuropathy—But Can We Also Address Mechanisms?”1 at the 2018 IASP World Congress on Pain in Boston. Treatment of painful diabetic neuropathy is still insufficient and has so far almost exclusively been based on symptomatic management, with compounds that unspecifically act on neuronal hyperexcitability. Improvement in management is dependent on treatments that better target molecular abnormalities in PDN. Thus, Dr. Jensen reviewed the outcomes of previous randomized controlled trials in PDN and discussed the possibilities for management.

Determining Neuropathy

A diabetes patient having pain in their feet does not necessarily mean that they have fallen to painful diabetic neuropathy. Pain can be nociceptive or neuropathic, or be a cause of other comorbidities. “When we see a patient, we have to take these things into account before we conclude the patient into a specific trial,” said Dr. Jensen.

Dr. Jensen outlining the four major types of diabetic neuropathy, and noted that sometimes a combination of these will be present in patients:

  • peripheral neuropathy
  • proximal neuropathy
  • autonomic neuropathy
  • and focal neuropathy.

Diabetic neuropathy is a progressive disorder, according to Dr. Jensen, and there is no gold standard for defining the condition. Patients should be assessed based on medical history, further evaluation and tests to confirm the neuropathy between the small and large fiber types, or a combination of the two.

Treatment

While current treatment is promising, many insufficiencies still remain. Dr. Jensen outlined a number of common symptoms for diabetic neuropathy, including numbness and similar unpleasant sensations in the feet/calves, as well as hypertension and allodynia, which, according to Dr. Jensen, is only seen in about 5 to 10% of patients.

Dr. Jensen found two promising treatments for diabetic neuropathy:

Angiotensin-converting enzyme inhibitors (ACEIs) – For example, in one study,2 researchers examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine monocyte chemoattractant protein-1(MCP-1) and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor (lisinopril).

They found improved renal function: proteinuria decreased from 410 +/- 662 mg per 24 h to 270 +/- 389 mg per 24 h; creatinine clearance rose from 61 +/- 26 to 77 +/- 41 ml/min; urinary MCP-1 levels decreased from 0.456 +/- 0.22 ng/mg creatinine to 0.08 +/- 0.096 ng/mg creatinine; and the change in uMCP-1 correlated significantly (r = 0.61, P < 0.001) with the change in proteinuria.

Alpha-lipoic acid (ALA) – One systematic review,3 found that current data provides evidence for the benefits of ALA in DPN treatment at a dose of 600 mg per day, for at least 3 weeks with minimal side effects. It demonstrated effectiveness in treating DPN through multiple mechanisms to modulate pathophysiology and control symptoms. In addition, ALA exhibited activity in weight management and insulin sensitivity.

Researchers noted that ALA “is worth considering [as a treatment] because commonly prescribed medications have unclear mechanisms, more pronounced adverse effects, and are more expensive than ALA.”

For non-pharmacological treatment, Dr. Jensen reviewed the promising nature of spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy, recounting two studies5,6 from the Netherlands that showed promising results.

Shifting his attention over to the guidelines for evidence4 of pharmacological and non-pharmacological treatment, Dr. Jenson stated the strong evidence for anticonvulsants such as pregabalin; moderate evidence of antidepressants such as amitriptyline, venlafaxine, and duloxetine; and moderate evidence for opioids such as dextromethorphan, morphine sulphate, tramadol, and oxycodone.

In addition, Dr. Jensen reviewed the numbers needed to treat (NNT) values7 for diabetic neuropathy, saying that, “we’ve seen a seismic shift over the years in the numbers needed to treat [shifting from] a 4, 5, 6, to a 7, 8, 10…It is still rather disappointing in that the numbers needed to treat are high, and there is still an unmet need for better treatment for the patient.”

Not Quite There

Dr. Jensen also reviewed two other promising, but underwhelming treatments for DN and PDN:

Capsaicin 8% patch – In one 12-week, randomized, double-blind, placebo-controlled study,8 in 369 patients (capsaicin 8% patch, n = 186; placebo patch, n = 183) with painful diabetic peripheral neuropathy (PDPN), capsaicin 8% patch treatment provided modest pain relief and sleep quality improvements versus a placebo patch.

Sodium channel blockers - Sodium channels represent an appealing target for researchers involved in the development of new and safer drugs useful in the treatment of neuropathic pain, according to authors Rivara et al.9 Researchers have currently identified and characterized selective compounds against NaV1.7 or NaV1.8 voltage-gated sodium channels, which are currently in the pipeline.

“There is light at the end of the tunnel. If we are more careful with selecting our patients, we may be able to find better patient response,” remarked Dr. Jensen. It’s easy to see that the success of treatment for both painful and non-painful diabetic neuropathy is still ongoing, and more research needs to be done. Dr. Jensen concluded by saying that current treatment is still insufficient both on the pharmacological side and the non-pharmacological side. He urged those in attendance on the need for a disease-modified treatment for both DN and PDN.

 

References

1. Jensen TS. “Symptomatic Treatment of Pain Diabetic Neuropathy—But Can We Also Address Mechanisms?” Presented at 2018 IASP World Congress on Pain, September 12-16, in Boston, MA.

2. Amann B, Tinzmann R, Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care. 2003;26(8):2421-2425.

3. Nguyen N, Takemoto JK. A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy. J Pharm Pharm Sci. 2018;21(1s):177s-191s.

4. American Academy of Neurology. Treatment of Painful Diabetic Neuropathy. 2011. Available at: https://www.aan.com/Guidelines/Home/GetGuidelineContent/480. Accessed September 21, 2018.

5. Slangen R, Schaper NC, Faber CG, et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized controlled trial. Diabetes Care. 2014:37(11):3016-3024.

6. van Beek M, Geurts JW, Slangen R, et al. Severity of Neuropathy Is Associated With Long-Term Spinal Cord Stimulation Outcome in Painful Diabetic Peripheral Neuropathy: Five-Year Follow-up of a Prospective Two-Center Clinical Trial. Diabetes Care. 2018;41(1):32-38.

7. Snyder MJ, Gibbs LM, Lindsay TJ. Treating Painful Diabetic Peripheral Neuropathy: An Update. Am Fam Physician. 2016;94(3):227-234.

8. Simpson DM, Robinson-Papp J, Van J, et al. Capsaicin 8% patch in painful diabetic peripheral neuropathy: a randomized, double-blind, placebo-controlled study. J Pain. 2017;18(1):42-53.

9. Rivara M, Zuliani V. Novel sodium channel antagonists in the treatment of neuropathic pain. Expert Opin Investig Drugs. 2016;25(2):215-26.

Next summary: Translating Trials into Practice from a Primary Care Perspective
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