Aims: The study aimed to assess the efficacy and tolerability of different combina7ons of first-line drugs for the treatment of diabe7c peripheral neuropathic pain (DPNP).
Methods: OPTION-DM was a mul7centre, randomised, double-blind, crossover trial in pa7ents with DPNP with mean daily pain numerical ra7ng scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Par7cipants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisa7on schedule stra7fied by site using permuted blocks of size 6 or 12, to receive one of 6 ordered sequences of the 3 treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxe7ne supplemented with pregabalin (D-P), each pathway las7ng 16 weeks. The primary outcome was the difference in 7-day average daily pain during the final week of each pathway.
Results: 140 pa7ents were randomly assigned, and 130 started a treatment pathway (with 84 comple7ng at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6.6 (SD 1.5) at baseline to 3.3 (1.8) at week 16 in all 3 pathways. The mean difference was -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. Mean NRS reduc7on in pa7ents on combina7on therapy was greater than in those who remained on monotherapy (1.0 [SD 1.3] vs. 0.2 [1.5]). Adverse events were predictable for the monotherapies. Increase in dizziness in the P-A pathway, in nausea in the D-P pathway, and in dry mouth in the A-P pathway were observed. Conclusions: All 3 treatment pathways and monotherapies had similar efficacy. Combina7on treatment improved pain relief in pa7ents with subop7mal pain control with a monotherapy and was well tolerated.
Comments. Pain is a deeply subjec7ve and personal experience. It is well recognised that DPNP can be very distressing and hard to treat. Most guidelines for DPNP recommend amitriptyline, duloxe7ne, pregabalin, or gabapen7n as ini7al analgesic treatment for DPNP, but there is liale compara7ve evidence on which one is best or whether they should be combined. The OPTION-DM trial showed that all three treatment pathways reduced the NRS by 3.3 (approx. half the baseline NRS) and were of similar efficacy. Monotherapy resulted in significant pain relief only in just over a third of par7cipants (=who reached NRS <3). It also showed that combina7on treatment was well tolerated and led to improved pain relief in pa7ents with subop7mal pain control with a monotherapy - an addi7onal 18% of pa7ents reaching NRS <3 and 14% reaching 50% pain relief. One key strength of the OPTION-DM trial was its pragma7c study design, mirroring current neuropathic pain management pathways, where pa7ents are started on monotherapy and escalated to combina7on therapy, thereby allowing the outcomes of this study to be readily generalisable. The OPTION-DM trial is the largest and longest ever, head-to-head, crossover neuropathic pain trial. The findings are likely to influence DPNP algorithms globally and may even extend to other neuropathic pain syndromes. Importantly, this study was designed and delivered by key, loved, members of Neurodiab - Prof. Solomon Tesfaye and Dr Dinesh Selvarajah, who jointly with the collabora7ve network of colleagues, both in UK and the EU, many of whom are also Neurodiab members, have delivered a stellar, pivotal moment in DPNP clinical research.
Prashanth Vas
References. Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, Rajbhandari S, Sharma S, Rayman G, Gouni R, Alam U, Cooper C, Loban A, Sutherland K, Glover R, Waterhouse S, Turton E, Horspool M, Gandhi R, Maguire D, Jude EB, Ahmed SH, Vas P, Hariman C, McDougall C, Devers M, Tsatlidis V, Johnson M, Rice ASC, Bouhassira D, BenneK DL, Selvarajah D; OPTION-DM trial group. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxeSne supplemented with pregabalin for the treatment of diabeSc peripheral neuropathic pain (OPTION-DM): a mulScentre, double-blind, randomised crossover trial. Lancet. 2022 Aug 27;400(10353):680-690. doi: 10.1016/S0140-6736(22)01472-6. Epub 2022 Aug 22.
