For the treatment of diabetic peripheral neuropathy pain (DPN), certain antidepressants and anticonvulsants ranked best, according to a systematic review, reports MedPage Today.
The findings by lead author Dr Julie M Waldfogel, of Johns Hopkins Hospital in Baltimore, and colleagues showed that the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine were more effective at reducing DPN pain compared with placebo, based on moderately strong evidence.
Lower-grade evidence found that pregabalin and oxcarbazepine were also more effective at reducing pain due to DPN versus placebo. Similar findings were reported for tricyclic antidepressants, atypical opioids, and botulinum toxin.
“Our results generally support the effectiveness of the three drugs approved by the FDA for the treatment of DPN pain: duloxetine, pregabalin and tapentadol, which is not surprising,” Waldfogel is quoted in the report as saying. “Our results also continue to suggest that other medications such as oxcarbazepine, TCAs([tricyclic antidepressants), venlafaxine, and tramadol may be effective.”
The findings add to the latest treatment guidelines, published in 2011 by the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine & Rehabilitation, which recommended pregabalin as an established effective treatment method based on the strongest evidence of research. The current guideline also notes that venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, capsaicin, and opioids including morphine sulfate, tramadol, and oxycodone controlled-release are also potentially effective treatment methods, based on lower-grade evidence.
“Treating pain related to diabetic peripheral neuropathy is so important – but it’s also important to know which treatments actually work,” said Waldfogel. “New studies come out every year, and we felt it was important to update and synthesize the existing literature around medications for the treatment of diabetic peripheral neuropathy pain.”
The report says Waldfogel and colleagues explained that their review, an update to a 2014 systematic review by Dr Marcio Griebeler, and colleagues – which determined that pregabalin was more effective at treating DPN pain versus a placebo (SMD -0.55; 95% CI; -0.94 to -0.15) – aimed to build on the findings with additional data. The new review assessed available studies appearing in the Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov, for a total of 106 randomised controlled trials, consisting of 57 from the existing systematic review, 24 additional studies, and 25 unpublished studies. Waldfogel noted that there were no previous reviews for pharmacologic DPN treatment that included data from ClinicalTrials.gov – “which we felt was a missed opportunity.”
The findings from the new review, which concluded that SNRIs are an effective treatment, while gabapentin is ineffective, were in line with Griebeler’s group’s previous reports. However, the Waldfogel review also found that pregabalin was an effective treatment (SMD -0.34; 95% CI, -0.50 to -0.18), yet less significant than Griebeler et al’s assessment.
“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,” Waldfogel is quoted as saying. “When those results were combined with published studies in a meta-analysis, we found a reduction in effect compared to previous reviews. We were also interested to learn that gabapentin and topical capsaicin 0.075%, although often used for DPN pain, were ineffective.”
Of those on oral agents, dropout rates due to adverse side effects ranged up to 70% for opiates and atypical opiates, most commonly due to constipation, nausea, and somnolence, while dropout rates were lowest among patients on topical agents.
The authors said that although they aimed to determine the differences between pharmacological treatments and the effects on quality of life, the majority of the studies included in the review did not report specific quality-of-life values, leading to a lack of sufficient evidence for comparisons.
The short duration of most of the trials included was a large limit to the findings, particularly related to the potential risks of long-term opioid use, the team noted, adding that follow-up research is required on the long-term effects of pharmacotherapy for chronic DPN pain, specifically focusing on outcomes beyond 6 months.
Objective: To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life.
Methods: We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE).
Results: We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects.
Conclusions: For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients’ quality of life.
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 Robinsson