ARTICLE IN BRIEF
A leading pain specialist discusses updated findings from 2011 guidelines on managing diabetic peripheral neuropathy and results from an independent 2014 meta-analysis funded by the Mayo Foundation for Medical Education and Research.
Although a number of pharmacological treatment options may help patients with painful diabetic peripheral neuropathy, longer and more carefully-designed studies are needed — especially with regard to evaluating quality of life, according to a systematic literature review conducted for the Agency for Healthcare Research and Quality (AHRQ) at the Department of Health and Human Services.
The analysis, published in the March 24 online edition of Neurology, updated the review used to inform the Academy of Neurology's 2011 guidelines on diabetic peripheral neuropathy (DPN) as well as findings from an independent 2014 meta-analysis funded by the Mayo Foundation for Medical Education and Research.
Neurology Today asked lead author Julie M. Waldfogel, PharmD, CPE, a pain specialist at Johns Hopkins University Hospital in Baltimore, to discuss the results and their clinical implications.
WHAT NEW FINDINGS WERE MADE?
Our findings on the effectiveness of gabapentin and capsaicin cream differed from the 2011 guidelines. They were considered probably effective in 2011, but we found no evidence to support their use. Although gabapentin and pregabalin work in the same way and both are often used interchangeably, we found gabapentin is no more effective than placebo. Pregabalin is probably effective, but there were some signs of reporting bias and low levels of evidence. Also, 0.075 percent topical capsaicin did not work better than placebo, and there was only one study on an 8 percent capsaicin patch, so we were not able to evaluate its effectiveness. We also found little evidence that dextromethorphan is effective, and could not draw any conclusions about the synthetic cannabinoid nabilone, or the extract nabiximols, because we found only one study for each of them.
HOW MANY STUDIES WERE INCLUDED?
Our analysis included 106 randomized clinical trials, including 57 from the 2014 analysis and 24 additional randomized clinical trials that included 25 different comparisons. We also reviewed 25 unpublished trials listed on clinicaltrials.gov between 2013 and 2014, 18 of which were listed as being completed. The 2011 AAN review and guidelines included studies up to 2008. The most recent review of randomized controlled trials in 2014 included studies published as of April of that year. This last review did not cover some of the newer treatments or include evidence on other patient-reported outcomes such as health-related quality of life, nor did it include unpublished studies from clinicaltrials.gov.
WHICH MEDICATIONS WERE FOUND TO HAVE EFFICACY?
It is important to note that because we included data from completed but unpublished studies included on clinicaltrials.gov, we saw an overall reduction in effect size for many of the medications. Our findings support three drugs for DPN pain: duloxetine, pregabalin, and tapentadol. Some drugs that have not been approved also may be effective, according to newer trials. These include oxcarbazepine, venlafaxine, tricyclic antidepressants as a class, tramadol, and botulinum toxin, although all of them carry substantial risk of side effects.
There was moderate evidence that the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine are effective, but low strength of evidence for botulinum toxin, pregabalin, oxcarbazepine, tricyclic antidepressants, and atypical opioids. The effect size was small for both pregabalin and oxcarbazepine. There were only two studies on imipramine, which we found is effective but with a low strength of evidence, and we were unable to draw conclusions for desipramine or amitriptyline due to a lack of evidence.
We found two randomized trials that compared botulinum toxin against placebo and were not included in the 2014 review. These indicated that botulinum toxin was more effective than placebo in relieving pain, and although overall the data showed a moderate to large effect size, they had a low strength of evidence.
WHAT FINDINGS WERE MADE ABOUT QUALITY OF LIFE?
Unfortunately, there was insufficient evidence to draw any conclusions about the effects of any treatment on quality of life, something that future studies need to assess. Because quality of life was reported inconsistently, we were limited to counting studies with the most relevant quality of life measures. We identified 32 studies that reported quality of life, but many studies did not report specific quality-of-life values, only whether or not the results were statistically significant.
WHAT DID YOU FIND ABOUT SIDE EFFECTS?
All of the effective drugs had more than 9 percent of participants who dropped out because of adverse side effects in their respective studies. Overall, dropout rates ranged from 2.5 percent up to 70 percent for oral medications, and from 0 percent to 8.6 percent for others. Those reported most often for serotonin-norepinephrine reuptake inhibitors and anticonvulsants were dizziness, nausea and somnolence. Studies of tricyclic antidepressants reported xerostomia, somnolence, and insomnia; for opioids and atypical opioids, the most common adverse effects were constipation, nausea, and somnolence.
WHAT DID YOU FIND ABOUT OPIOID MEDICATIONS?
Long-term use of opioids is not recommended for chronic pain, and there was little evidence that support the use of atypical opioids. In addition to a lack of evidence about efficacy, especially long-term studies, these carry the risk of abuse, misuse, and overdose. For typical opioids, oxycodone was not more effective than placebo and the atypical opioids, tramadol and tapentadol, were more effective than placebo, but the effect size was moderate and there was a low strength of evidence. Also, in the studies of tapentadol, the trial methodology was inconsistent with standards for pain trials, including using nonstandard primary pain outcomes and withdrawal study methodology. These are of special concern for studies on opioids.
WHAT WERE SOME LIMITATIONS IN YOUR REVIEW?
We excluded studies including mixed populations of those with diabetic peripheral neuropathy and other types of neuropathy, which may have excluded some relevant data. Also, because studies often reported multiple assessment tools for pain, sometimes with conflicting results, our choices of tools may have affected our findings. We used pain scales, but these have many limitations because they evaluate pain only at one point in time, and do not address other important aspects of pain treatment, such as improved function.
We also could not assess long-term clinical outcomes and harms, including continued effectiveness with progression of DPN or long-term side effects, long-term effect on function, or diabetic complications. This is particularly important for atypical opioids, which we found were effective in short-term studies. New guidelines and position papers recommend against using opioids for chronic pain conditions given a lack of evidence for long-term benefits and increasing evidence of serious risks.
DID THE REVIEW IDENTIFY RESEARCH GAPS?
Additional studies are needed to evaluate longer-term outcomes for better clinical decision-making, patient choice, and clinical practice guidelines. Few studies have been done on the long-term effects of these drugs and their impact on quality of life. Most clinical trials that we reviewed were of just three months or shorter duration, although these medications are being used for long-term pain management. Also, we could not make any recommendations based on direct head-to-head drug comparisons. None of the comparison studies included more than one medication, and there was insufficient evidence about drug-to-drug comparisons.
LINK UP FOR MORE INFORMATION:
•. Waldfogel JM, Nesbit DA, Dy SM, et al Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review http://http://www.neurology.org
2017; Epub 2017 Mar 24.
•. Bril V, England JD, Franklin GM, et al Evidence-based guideline: Treatment of painful diabetic neuropathy – Report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation https://http://www.aanem.org
/getmedia/66da702a-0a02-44e0-9490-853dc7078466/MUS-11-0157_FINAL.pdf. Muscle Nerve
•. Griebeler ML, Morey-Vargas OL, Brito JP, et al Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis http://annals.org/aim/article/1920504/pharmacologic-interventions-painful-diabetic-neuropathy-umbrella-systematic-review-comparative-effectiveness. Ann Intern Med 2014;161:639–649