Three treatment pathways, including combination therapy if monotherapy failed, were equally effective.

For patients with diabetic peripheral neuropathy pain, most guidelines recommend initial treatment with amitriptyline, duloxetine, pregabalin or gabapentin; however, monotherapy with any of these agents often provides incomplete relief, and head-to-head comparisons are rare. Clinicians sometimes add a second agent when monotherapy fails for their patients, but this strategy has not been assessed in high-quality studies.

Researchers defined three 16-week pragmatic treatment pathways, with each starting agent titrated to maximal tolerated dose over six weeks then supplemented (if the first agent provided suboptimal relief) by a second agent for the final 10 weeks. The pathways were (1) amitriptyline supplemented by pregabalin, (2) duloxetine supplemented by pregabalin, and (3) pregabalin supplemented by amitriptyline. Using a crossover design, 130 patients with painful diabetic neuropathy (mean duration, five years) were randomised to begin one of the three pathways and then, after a one-week washout, to begin one of the other pathways for 16 weeks, and finally to receive the third pathway for 16 weeks. Six pathway orders were possible.

Mean pain intensity decreased from 6.6 (on a 10-point scale) at baseline to 3.3 during the final week of each pathway, with no significant differences between pathways at any point. About 35% of patients had adequate pain relief with monotherapy, and another 15% achieved adequate relief with addition of a second agent.

Comment: This study supports adding a second agent when monotherapy fails to adequately relieve painful diabetic neuropathy. It also suggests that the medications commonly used for this condition are equally effective for monotherapy or combination therapy. However, three caveats are worth mentioning. First, the known side effects of these drugs were seen frequently in this trial (e.g. dry mouth and sedation with amitriptyline, dizziness with pregabalin, nausea with duloxetine). Second, the trial had no placebo group. And third, the researchers did not address another reasonable strategy – sequential monotherapy (i.e. switching from one single drug to another before moving to combination therapy).
BRUCE SOLOWAY, MD
Associate Professor Emeritus of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

Tesfaye S, et al. Comparison of amitrip­tyline supplemented with pregabalin, pregabalin supplemented with amitrip­ tyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION­DM): a multicentre, double­blind, randomised crossover trial. Lancet 2022; 400: 680­-690.

This summary is taken from the following Journal Watch title: Neurology.