Amitriptyline, duloxetine, and pregabalin each effective in decreasing pain from diabetic peripheral neuropathy; combinations even better

Reference

Tesfaye S, Sloan G, Petrie J, et al, OPTION-DM trial group. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. Lancet 2022;400(10353):680-690.

Synopsis

This was a complex study design, so be patient while I try to explain it. The researchers enrolled 130 adults with diabetes and pain associated with distal symmetrical polyneuropathy for at least 3 months. In this cross-over trial, the participants were randomly assigned to three 16-week pathways separated by a 2-week washout period: oral amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P). Each pathway started with a 2-week period in which doses of medication were titrated to the maximum tolerated dose. This was followed by 6 weeks of maintenance monotherapy. At the end of 6 weeks, as we would do in clinical practice, those with pain <= 3/10 were classified as responders and maintained on monotherapy for 10 weeks. Nonresponders then received the second drug for 10 weeks. During the subsequent 10 weeks, the researchers titrated medication doses to maintain pain levels at <= 3/10. At the end of 16 weeks the researchers stopped all study drugs for a 2-week washout period and then the participants started the next drug combination. Whew! Most (84%) of the participants had type 2 diabetes and were white (94%). Although 130 started the first pathway, only 97 and 84 began a second and third pathway, respectively. At the end of 6 weeks of monotherapy, the proportion of responders was similar for amitriptyline (37%), duloxetine (32%), and pregabalin (34%). At the end of 16 weeks, the proportion of responders was similar for A-P (48%), D-P (43%), and P-A (47%). Additionally, the authors found that at the end of each evaluation period, the participants had similar degrees of improvement in pain regardless of agent. Finally, most adverse events were mild and similar across all 3 paths, with the 3 exceptions summarized in the table.