Parts of this report have been reproduced with permission from Tesfaye et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Parts of this chapter have been reproduced from the published OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) protocol.2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.3
Scientific background
There are currently 3.9 million people in the UK with a diagnosis of diabetes and, if the numbers continue to increase at the current rate, it is expected that this will increase to 5.3 million people by 2025.4 Diabetic peripheral neuropathic pain (DPNP) is a serious complication affecting up to 20–26% of these patients.5,6 With the prevalence of diabetes set to increase by epidemic proportions over the next decade, DPNP will pose a major treatment challenge.7,8
Diabetic peripheral neuropathic pain causes burning, deep aching and ‘electric shock’-like lancinating (also described as ‘stabbing or knife-like’) pains; contact pain, often with day-time clothes and bedclothes (allodynia); pain on walking, often described as ‘walking barefoot on marbles’ or ‘walking barefoot on hot sand’; sensations of heat or cold in the feet; a persistent achy feeling in the feet and cramp-like sensations in the legs.8 With advanced disease, the pain can extend above the feet and may involve the whole of the legs. When this is the case, then there is often upper limb involvement also. Moderate to severe unremitting lower limb pain is present in over 70% of sufferers6,9 and can cause insomnia, poor quality of life (QoL), unemployment and depression.10–13
The mainstay of treatment for DPNP is pharmacotherapy. The National Institute for Health and Care Excellence (NICE) clinical guideline 17314 recommends a choice of amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment. All are licensed treatments for DPNP, except amitriptyline, which has been used off-licence for more than 25 years. There is moderate evidence for the efficacy of each drug based on Cochrane reviews15–18 and meta-analyses,19–21 but the best we can hope for with any monotherapy is 50% pain relief in 50% of patients.14 This is often accompanied by side effects (dry mouth, constipation, sedation, dizziness, falls, nausea, oedema, etc.) in around 10–20% of patients, depending on dose. NICE recommends combination treatment if initial treatment is not effective (the majority).14 However, as NICE points out, recommendations are not based on robust evidence because (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 end points or short duration of follow-up, and (3) many randomised controlled trials (RCTs) lacked appropriate health-related quality of life (HRQoL) measures, including functionality, and failed to measure the impact of drug-related adverse effects on health economics and QoL.14 A RCT is, therefore, needed to address these deficiencies.
Rationale for research
Recent Cochrane reviews,15–18 meta-analyses,19–21 consensus guidelines22–24 and NICE clinical guidance 17314 support the choice of amitriptyline (25–75 mg/day), duloxetine (60–120 mg/day) and the α2δ agonists pregabalin (300–600 mg/day) and gabapentin (0.9–3.6 g/day) as first-line agents for DPNP. However, these recommendations are not based on solid evidence.
Comparator studies
Two small randomised double-blind crossover short-duration (5 weeks’ follow-up) studies compared amitriptyline with pregabalin (n = 51)25 and amitriptyline with duloxetine (n = 58)26 in DPNP. The studies were underpowered to detect any differences in pain relief between the drugs. Another underpowered, and short (4 weeks), RCT compared amitriptyline (n = 27), duloxetine (n = 28) and pregabalin (n = 28),27 and found no differences between the groups. The lack of head-to-head studies led to an indirect comparison of the efficacy and tolerability of duloxetine with pregabalin, using placebo as a common comparator, but this comparison found no difference in 24-hour pain severity between the two.28
Combination studies
Low-dose combination therapy with gabapentin and morphine was more effective than higher doses of either,29 although, curiously, there was no difference between placebo and gabapentin.30 Finally, the COMBO-DN (COmbination vs Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy) study,31 which, to the best of our knowledge, is the largest combination study in DPNP (n = 804), assessed whether or not combining standard doses of duloxetine (60 mg/day) and pregabalin (300 mg/day) was superior to maximum doses of either. The COMBO-DN study31 also compared head to head the standard doses of duloxetine and pregabalin and found no difference in the change in 24-hour average pain or number of adverse events (AEs) between standard-dose combination therapy and high-dose monotherapy.31 Although the standard dose of duloxetine was superior to pregabalin, there was equivalent efficacy with pregabalin at higher doses.31
Published economic evaluations
To date, no trial has provided conclusive evidence regarding the cost-effectiveness of amitriptyline, duloxetine and pregabalin for DPNP. Wu et al.32 conducted a cost–utility analysis of duloxetine compared with usual care as part of an open-label study extension and concluded that duloxetine was a dominant treatment (i.e. more effective and less costly). However, methodological issues limit the generalisability of this conclusion. Beard et al.33 developed a short-term decision tree to estimate alternative treatment sequences that include duloxetine. A standard treatment sequence was defined as amitriptyline, gabapentin and then opioid-related treatment. Duloxetine was evaluated as a first-, second-, third- or fourth-line therapy. First-line use of duloxetine was both the most effective and most cost-effective treatment strategy. O’Connor et al.34 compared the costs and quality-adjusted life-years (QALYs) of first-line desipramine, duloxetine, gabapentin and pregabalin, and concluded that desipramine and duloxetine may be more cost-effective than gabapentin or pregabalin for first-line treatment of DPNP. In 2012, de Salas Cansado et al.35 conducted an economic evaluation of pregabalin compared with usual care in the management of community-treated patients with refractory painful diabetic peripheral neuropathy in Spain. de Salas Cansado et al.35 compared costs and QALYs from a Spanish NHS and societal perspective and concluded that pregabalin may be cost-effective. The limited published evidence highlights the need for a definitive evaluation of the costs and health benefits of alternative treatment sequences for DPNP. This evidence would inform NHS guidance and commissioning and ensure an efficient use of limited health resources.
In summary, there is a lack of head-to-head studies of current drugs and their combinations, highlighting the need for carefully designed RCTs, involving patients recruited from both primary and secondary care, to identify the most cost-effective and best-tolerated treatment pathway for DPNP.
Intervention
The OPTION-DM trial was a randomised crossover trial of treatment pathways to evaluate the superiority of at least one pathway [i.e. amitriptyline supplemented with pregabalin (A-P), duloxetine supplemented with pregabalin (D-P) and pregabalin supplemented with amitriptyline (P-A)] in reducing the 7-day average 24-hour pain in patients with DPNP.
Each treatment pathway consisted of two periods (i.e. 6 weeks’ monotherapy followed by 10 weeks’ combination therapy).
Why exclude gabapentin?
The rationale for not studying two α2δ agonists (i.e. pregabalin and gabapentin) is that:
Why examine treatment pathways?
Although a head-to-head RCT of individual drugs and a separate RCT of combination therapy could be designed, in our opinion an 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. Only a minority of patients will either have massive benefit from monotherapy [i.e. 24-hour pain scores of < 3 points on a Numeric Rating Scale (NRS)] and will not need another agent or will not tolerate monotherapy (or monotherapy will be completely ineffective) and will be switched to another agent. Therefore, the OPTION-DM trial, which examined the whole treatment pathway, captured more clinically relevant outcomes than artificially designed head-to-head monotherapy or combination studies. Hence, the outcomes of this study will be readily generalisable to current UK clinical practice.
Which treatment pathways?
The three treatment pathways studied in the OPTION-DM trial were (1) A-P, (2) P-A and (3) D-P.
We did not examine the pathway of pregabalin supplemented by duloxetine because of the COMBO-DN study findings.31 In the COMBO-DN study, there was no difference in pain reduction if pregabalin was added to duloxetine, or vice versa.31 However, duloxetine was superior to pregabalin as an initial treatment, is a once daily preparation and is also the cheaper option in the UK. There is, therefore, a good rationale for starting patients on duloxetine and then adding pregabalin in combination. Finally, as both amitriptyline and duloxetine are antidepressants, there was little rationale for combining both.
Efficient design with 16-week treatment pathways
This was an efficiently designed head-to-head crossover RCT,37 with each patient undergoing all pathways. The duration of monotherapy in each pathway was at least 6 weeks, which is an adequate duration to assess treatment effect and whether or not combination therapy is indicated.23,37 The subsequent 10-week combination therapy in patients with partial benefit from monotherapy is adequate to assess stabilised treatment outcomes.31
Objectives
The main aims of this study were to determine the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP.
Efficacy objectives
The efficacy objectives were to evaluate if at least one of the three pathways is superior to the other pathways in improving self-reported pain, as measured by a NRS (the primary outcome), tolerability, QoL and cost-effectiveness over a 16-week treatment period. The secondary efficacy objective was to evaluate if at least one monotherapy is superior to a different monotherapy in improving the same outcomes.
Safety objective
The safety objective was to describe AEs and serious adverse events (SAEs) data (summarised both at patient level and event level) between the different treatment pathways.
Subgroup study objectives
We conducted a subgroup study to investigate if patient phenotypes (demography, type of pain, assessments of mood, sleep, etc.) predict response to treatment.
