Diabetic peripheral neuropathic pain (DPNP) is a common and distressing condition. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as an initial analgesic treatment for DPNP; however, there exists little comparative evidence on which one is best or whether we should combine them. 

A recent study (OPTION-DM) assessed the efficacy and tolerability of different combinations of first-line drugs for the treatment of DPNP. It enrolled patients with DPNP with a mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) and randomized them (1:1:1:1:1:1) to receive one of six ordered sequences of the three treatment pathways: amitriptyline with pregabalin supplementation (A-P), pregabalin with amitriptyline supplementation (P-A), and duloxetine with pregabalin supplementation (D-P), with each pathway lasting 16 weeks. It gave monotherapy for six weeks and then supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. It titrated both treatments towards the maximum tolerated dose (75 mg/day for amitriptyline, 120 mg/day for duloxetine, and 600 mg/day for pregabalin) and assessed the difference in 7-day average daily pain during the final week of each pathway. 

The study screened 252 patients, randomly assigned 140 patients, started a treatment pathway in 130 (with 84 completing at least two pathways), and analyzed the primary outcome.

The 7-day average NRS scores at week 16 decreased from a mean 6·6 at baseline to 3·3 at week 16 in all three pathways. The mean difference was noted as -0·1 for D-P versus A-P, -0·1 for P-A versus A-P, and 0·0 for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was more significant than in monotherapy patients. Predictable adverse events emerged for the monotherapies, such as a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. 

This largest and longest-ever head-to-head, crossover neuropathic pain trial showed similar analgesic efficacy in all three treatment pathways and monotherapies. Combination treatment was well tolerated and caused improved pain relief in patients with suboptimal pain control with monotherapy.

Lancet. 2022 Aug 27;400(10353):680-690. doi: 10.1016/S0140-6736(22)01472-6.