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Painful Diabetic Neuropathy: What Is Best Rx—Pain Reduction or Improved Quality of Life?

April 10, 2017
A new systematic review has found a number of agents appear more effective than placebo at treating pain related to diabetic peripheral neuropathy, but significant information is still lacking, like information on patient quality of life and long term use of such drugs.

Interview with Julie M. Waldfogel, PharmD, CPE

The question over how to qualify improvement among pain patients—reduction in pain or improvement in quality of live (QOL)—has been raised after the recent publication of a review of treatments for diabetic peripheral neuropathy (DPN).1

While the review found a number of agents appear to be more effective than placebo at reducing pain, the data is still inconsistent on how these medications affect QOL, as well as how safety and effectiveness can be judged over time.

“Our experience [with the randomized controlled trials, RCTs] was not that past research lacked the measurement of QOL, but [how] those results were reported were highly inconsistent,” Julie M. Waldfogel, PharmD, CPE, told Practical Pain Management.

“Very few studies reported the actual change in QOL scale. So we are at a disadvantage in that if we want to use this information clinically, then we need to start reporting it more robustly,” she noted.

Also, while the current data supports the use of US Food and Drug Administration (FDA)-approved medications (eg, duloxetine, pregabalin, tapentadol), some of the available evidence for pregabalin (Lyrica) could be subject to bias. Studies looking at pregabalin often lacked consistent outcome reporting and a number of unpublished studies actually showed negative results, the researchers found.

“We were surprised by the evidence of reporting bias for pregabalin due to the number of completed studies on ClinicalTrials.gov that were never published,” said Dr. Waldfogel. “That data was certainly meaningful, since when those results were combined with published studies in a meta-analysis, we found a reduction in effect compared to previous reviews.”

“It’s difficult to say for certain why these studies were unpublished.  Regardless, we appreciate that the reporting requirements for ClinicalTrials.gov make using this information possible,” she said.

Patient with diabetes and foot ulcers.

QOL vs Pain Scale

Today, about 29.1 million people suffer from diabetes in the US, and around 30% to 50% will suffer from DPN, according to the Centers for Disease Control and Prevention.2-3

According to the American Diabetes Association, which recently published its own position statement on treating DPN, QOL is becoming an “emerging” topic of importance, as it may be regarded as a determinative factor of how well patients adhere and respond to different therapies for their neuropathic pain.4

For instance, some studies have suggested patients suffering from distal symmetric polyneuropathy (DSPN) treated with certain therapies, like duloxetine (Cymbalta), pregabalin, and gabapentin (Neurontin, others), showed significant improvements in QOL after taking these drugs.5-7

In the new review, which was published in Neurology,1 Dr. Waldfogel and colleagues culled together RCTs from 1966 through May 24, 2016, and aggregated data to assess patient outcomes, including pain intensity, health-related QOL, adverse effects, and dropout rates due to adverse effects. The review looked at 106 RCTs, including 24 additional published and 25 unpublished RCTs not found in a recent high-quality review by Griebeler et al.2 Follow-up duration for these studies ranged from 3 to 18 weeks.

Drugs for Reducing DPN-Related Pain:
Is Current Research Lacking?

According to the authors, the findings benefit from a substantial body of evidence, much of which generally supports the effectiveness of the 3 drugs currently approved by the FDAt for treating pain in DPN patients, specifically:

  • Duloxetine
  • Pregabalin
  • Tapentadol

At the same time, various agents have emerged with evidence of being possible off-label alternatives for the treatment of DPN-related pain, including:

  • Oxcarbazepine
  • Venlafaxine
  • Tricyclic antidepressants (TCA)
  • Tramadol
  • Botulinum toxin

Unfortunately, existing evidence on FDA-approved and nonFDA-approved therapies could be limited by the fact that a number of studies did not provide specific QOL values. Because of this, the review could not draw any conclusions about QOL from the existing research.

Also, with such a varied field of therapies, the risk of adverse effects tends to vary based on the medication. For instance, while studies looking at SNRIs (eg, duloxetine) reported patients suffering from dizziness, nausea, and somnolence, studies of TCAs found patients suffering from xerostomia, somnolence, and insomnia, the authors noted.

Dropout rates due to adverse effects related to oral agents also varied widely amongst the studies, from 2.5% to 70%. For nonoral drugs, dropout rates were far less frequent, 0% to 8.6%, the authors reported.

Also, most RCTs are relatively short, less than 3 months duration. This has prevented researchers from examining the long-term clinical effects of these medications, especially in the context of whether they have continued effectiveness with disease progression or a long-term effect on diabetes complications, the authors noted.

“It’s difficult to say for certain why there is a lack of long-term research and it’s probably multifactorial, and I’m sure funding is a part of that. We did find a few open-label extension studies of about a year, but those were not RCTs or placebo-controlled,” Dr. Waldfogel pointed out.

According to Dr. Waldfogel and her colleagues, there is now a need for additional studies that can look at the long-term aspects of these therapies. With that kind of information, it could help better inform clinical decision making and patient choice, as well as future clinical guidelines.

This study was funded under a contract from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. Full disclosures are made available at Neurology.org.

Last updated on: April 28, 2017
Continue Reading:
ADA Releases New Guidelines on Managing Diabetic Peripheral Neuropathy

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