Treatment choices for neuropathic pain should be guided by factors such as side-effects and costs of therapy because the three main recommended drug classes all have similar analgesic efficacy, researchers are arguing.
The message follows the OPTION-DM study, believed to be the largest and longest blinded neuropathic pain trial reported to date, comparing the efficacy of gabapentinoids, serotonin reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) in patients with diabetic peripheral neuropathic pain (DPNP).
Run over 16 weeks, the British trial randomly assigned 140 patients between three treatment pathways: pregabalin supplemented with amitriptyline (P-A), duloxetine supplemented with pregabalin (D-P) and amitriptyline supplemented with pregabalin (A-P).
By its close, there were significant falls in daily pain scores across all three pathways, halving from a mean of 6.6 out of 10 at baseline to 3.3 at week 16.
However, there was also little to separate each group, the researchers led by Professor Solomon Tesfaye of the Royal Hallamshire Hospital Diabetes Research Unit reported in The Lancet (link here).
The mean difference in pain scores between each pathway was minimal: -0·1 (98.3% CI -0.5 to 0.3) for D-P versus A-P, -0.1 (-0.5 to 0.3) for P-A versus A-P, and 0.0 (-0.4 to 0.4) for P-A versus D-P, and thus not significant.
“Despite large variations in the cost and availability of amitriptyline, duloxetine, and pregabalin across the world, it is reassuring that all three are similarly efficacious in relieving pain,” they wrote.
“Additionally, no significant differences were observed in the frequency of reported serious adverse events.”
And while the study was conducted in patients with diabetic neuropathy, the findings could be applied to treatment guidelines for chronic neuropathic pain treatment in general, the study investigators said.
“OPTION-DM is a pragmatic trial, mirroring current neuropathic pain management pathways, allowing the outcomes of this study to be readily generalisable,” they wrote.
In the trial, all patients were initially given monotherapy for six weeks, only receiving the combination medication if there was suboptimal pain relief (a daily pain rating greater than three out of 10).
A head-to-head comparison of the maximum tolerated doses for each monotherapy showed similar efficacies across the board, although monotherapy resulted in significant pain relief in just a third of participants.
However there were significantly fewer discontinuations due to adverse events with pregabalin than the other two. As expected, there was a significant increase in dizziness in the pregabalin pathway, nausea in the duloxetine pathway, and dry mouth in the amitriptyline pathway.
In a commentary published in the Lancet (link here), Dr Melissa Elafros and Dr Brian Callaghan of the University of Michigan’s Department of Neurology said the trial represented a major step forward.
“Importantly, [this] comparative effectiveness study provides much better evidence of similar efficacy across these three classes of medications,” they wrote.
“As a result, physicians should use factors other than efficacy (side-effects, cost, and other comorbidities) when determining which medication to start and add on for treatment of DPNP.”
The study also provided evidence that combination therapy should be standard practice, given its greater analgesic effect compared to monotherapy, they wrote.
“Not only did participants have significant pain relief, but they also had improvements in quality of life, depression, anxiety, and sleep outcomes, which are all key patient-oriented outcomes,” they added.
“We can confidently advise patients that our current treatments will help them in many meaningful ways.”
However the commentary noted that the study did not include sodium channel blockers and it will be important to include these in future comparative effectiveness studies. Similarly there is a need for future studies to address questions such as the efficacy of non-pharmacological interventions for DPNP; compare topical medications with oral medications, and a need to further define the role of opioids, the authors said.
“We need to better understand why the most common practice pattern is to start with gabapentin and switch to pregabalin if monotherapy is not successful, despite the fact that these medications are in the same medication class,” they added.