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Treating Diabetic Neuropathy

What treatments can improve pain and quality of life?

Diabetic neuropathy is a nerve disorder that the National Institute of Diabetes and Digestive and Kidney disease estimates affects about 60 to 70% of diabetic patients in some form, with the highest rates of neuropathy occurring in patients who have had diabetes for over 25 years. Although diabetic neuropathy can affect almost any organ in the body, the most common type of diabetic neuropathy is peripheral neuropathy. Peripheral neuropathy, which is often worse at night, results in tingling, numbness, and pain occurring in the hands, arms, fingers, legs, feet, and toes. The best way to prevent diabetic neuropathy is keeping glucose under control and maintaining a healthy weight, but for those who experience this painful condition, finding the best relief can often be difficult and confusing.

Previous meta-analysis studies have been published on effectiveness of different diabetic neuropathy treatments, but they do not include newer treatment options or show how treatments improve quality of life. They are also missing review data with how the meta-analysis was conducted. Building upon a previously published study from 2014, a new systemic review was conducted to “systemically assess the effect of pharmacological treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life” plus a search of PubMed and Cochrane Database of systemic reviews (reviews from 2011 – March 2016),  After the literature search, investigators identified the trial types, assessed the risk for bias, and pooled data on outcomes of pain intensity, health-related QOL, adverse effects, and dropouts due to adverse effects.

A total of 106 randomized controlled trials were used in the final systemic review, including trials analyzed by the previously published study. Only two medications, duloxetine and venlafaxine, had a moderate strength of evidence (SOE) compared to the low strength of evidence found with the remaining 12 study medications. As a class, serotonin-norepinephrine reuptake inhibitors (SNRIs) was found to be an effective treatment for diabetic neuropathy with the most commonly reported adverse effects of dizziness, nausea, and somnolence. Focusing on specific SNRIs, duloxetine was found to be effective for pain relief based on data from 2 new trials in addition to 5 trials from the previously published systemic review (Standardized mean difference (SMD) 21.33 [ Credible Interval (CrI) 21.82 to 20.86]). Venlafaxine and tricyclic antidepressants were also determine to be effective at relieving pain compared to placebo using the previous analysis’ data ((SMD 21.53 [CrI 22.41 to 20.65]; (SMD 20.78 [CrI 21.24 to 20.33])), but there was insufficient SOE to make any determination on the effectiveness of desvenlafaxine. Using 15 trials with a calculable SMD, pregabalin was determined to be effective at reducing pain compared to placebo (SMD 20.34; 95% Confidence Interval (CI) 20.50 to 20.18), but found to have a low SOE due to the inclusion of four unpublished studies causing potential bias. Pregabalin, as well as the other anticonvulsants included, had adverse effects of dizziness, nausea, and somnolence. Oxcarbazepine was also found to be an effective neuropathy pain reliever compared to placebo based on the previously published analysis (SMD 20.45 [CrI 20.68 to 20.21]).

Atypical opioids have a dual mechanism of action, norepinephrine reuptake inhibition and mu antagonism, which aids in a class wide effective pain relief compared to placebo, and more specifically tramadol and tapentadol were found to be effective vs placebo using new pooled data and data from the previously published analysis (SMD -0.68 [95% CI -0.80 to -0.56). The most common adverse effects reported for opioids were constipation, somnolence, and nausea. The last medication that was determined to be an effective pain reliever of diabetic neuropathy compared to placebo was botulinum toxin (SMD ranging from -0.96 to -0.79). Gabapentin, using five randomized controlled trials, was determined at two different doses to be ineffective at treating pain when compared to placebo (SMD 20.65, 95% CI 21.1 to 20.23; SMD 20.27, 95% CI 20.67 to 0.14; and SMD 20.20, 95% CI 20.46 to 0.06). Other agents that were determined to be ineffective treatments for diabetic neuropathy were typical opioids (oxycodone), topical capsaicin 0.075%, dextromethorphan, and mexiletine. Quality of life (QOL) could not be assessed due to incomplete reporting and insufficient SOE.

Limitations of this systemic analysis include lack of drug-drug comparison data, short duration of many of the included RCTs, and possible exclusion of relevant data due to exclusion of studies involving mixed origins of neuropathic pain. This analysis opens up the need for new trials comparing relative effectiveness of drug vs drug treatment for diabetic neuropathy.

Practice Pearls:

  • Pregabalin, oxcarbazepine, and tapentadol have shown to be effective vs placebo at relieving pain due to diabetic neuropathy and are also FDA approved for this indication.
  • Serotonin-norepinephrine reuptake inhibitors may be a good choice for relief of diabetic neuropathy pain and have the additional benefit of relieving depression that is commonly associated with diabetic neuropathy
  • Additional studies are needed to assess long-term pain relief effectiveness.

 

References:

“Nerve Damage (Diabetic Neuropathies) | NIDDK.” National Institutes of Health. U.S. Department of Health and Human Services. Web 05 April 2017

Julie M. Waldfogel, Suzanne Amato Nesbit, Sydney M. Dy, Ritu Sharma, Allen Zhang, Lisa M. Wilson, Wendy L. Bennett, Hsin-Chieh Yeh, Yohalakshmi Chelladurai, Dorianne Feldman, Karen A. Robinson. “Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life”. Neurology, 2017; 10.1212/WNL.0000000000003882 DOI: 10.1212/WNL.0000000000003882

 

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD