Abstract
BackgroundThe number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP.Methods/designA multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway.DiscussionThe study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment.Trial registrationISRCTN17545443. Registered on 12 September 2016.
Highlights
The number of people with diabetes is growing rapidly
There is moderate evidence for the efficacy of each drug based on Cochrane reviews [11,12,13,14] and meta-analyses [15,16,17], but the best we can hope for any monotherapy is 50% pain relief in 50% of patients [10]
As National Institute for Health and Care Excellence (NICE) points out recommendations are not based on robust evidence as: (1) there are few well-designed head-to-head studies comparing the first-line drugs and their combinations; (2) most studies were flawed with inadequate power, inappropriate endpoints, short duration of follow-up and (3) many randomised controlled trials (RCTs) lacked appropriate health-related Quality of Life (QoL) (HRQL) measures including functionality and failed to measure impact of drug-related adverse effects on health economics and QoL [10]
Summary
DPNP is a distressing and disabling condition which is often intractable to treatment. The examination of a treatment pathway as a whole is the most efficient and applicable to current UK clinical practice. This is because most patients are started on monotherapy and will require a second agent added in combination within a few months [41]. OPTIONDM, which will examine the whole treatment pathway, will capture more clinically relevant outcomes than artificially designed, head-to-head monotherapy or combination studies. The subsequent 10-week combination therapy in patients with partial benefit from monotherapy will be adequate to assess stabilised treatment outcomes [44]. The COMBO-DN study used fixed-dose-titration regimens regardless of treatment response This resulted in a dropout rate of 17% during monotherapy and 12% during combination therapy [44].
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