Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 15/35/03. The contractual start date was in June 2016. The draft report began editorial review in September 2021 and was accepted for publication in March 2022. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2022 Tesfaye et al. This work was produced by Tesfaye et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2022 Tesfaye et al.

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.

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).

Objectives

The main aims of this study were to determine the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP.

Study design

This was a randomised crossover trial of treatment pathways to evaluate the superiority of at least one pathway (i.e. A-P, D-P and P-A) in reducing the 7-day average 24-hour pain in patients with DPNP. Eligible patients were randomised to one of six treatment sequences, with equal allocation to sequences (1 : 1 : 1 : 1 : 1 : 1). Each sequence examined all three treatment pathways in random order. Each treatment pathway consisted of two phases (i.e. 6 weeks’ monotherapy followed by 10 weeks’ monotherapy or 10 weeks’ combination therapy based on response to treatment).

Figure 1 shows a schematic representation of the study schedule. Following the screening, consent and initial washout visits (i.e. weeks –2 to 0), the visits from week 0 to week 16 were repeated until all three treatment pathways were completed. Face-to-face assessments were completed at the week numbers indicated in Figure 1. Weekly telephone calls were carried out between study visits.

FIGURE 1.

Study schedule.

Trial approvals and registration

The trial was approved by the Yorkshire and the Humber – Sheffield Research Ethics Committee (reference 16/YH/0459) on 9 December 2016. The Medicines and Healthcare products Regulatory Agency issued the clinical trial authorisation on 23 June 2017 (reference 21304/0262/001-0001, EudraCT reference 2016-003146-89).

The trial was registered as ISRCTN17545443.

Participant eligibility criteria

Settings and locations where the data were collected

Initially, the trial planned to recruit participants from eight secondary care hospital sites across the UK. Additional sites were added during the trial, and a total of 21 sites were opened to recruitment during the course of the trial.

Potential participants were identified directly through the database and via clinics at participating centres, as well as via participant identification centres, podiatry clinics and general practice mail-outs. Recruitment strategies differed between sites to reflect the local organisational structure at each site.

Participant treatment and outcome data collection was carried out by the recruiting hospital site. All research activity at the site was carried out by hospital employees trained in OPTION-DM trial processes.

Screening, assessment of eligibility and consent

Prior to any study procedures being completed, participants were required to give written informed consent for the study. The participant was given sufficient time to ask questions, consider the study and discuss it with family/friends prior to providing consent, which was taken by medically qualified site investigators.

Eligibility for the study was assessed by the local investigator. Participants were required to stop all existing treatment for neuropathic pain, except paracetamol, if applicable. Treatments were tapered, usually over a period of 3 days followed by a 4-day washout period. Participants then entered the baseline period and the pain scores collected during this period were used to determine eligibility.

Randomisation

Randomisation was completed using the Sheffield Clinical Trials Research Unit (CTRU) online randomisation system (SCRAM). Participants were assigned to one of six sequences (allocation 1 : 1 : 1 : 1 : 1 : 1) based on a predetermined randomisation schedule and stratified by site using permuted blocks of sizes 6 or 12. The trial statistician created the randomisation schedule. Each sequence consisted of three treatment pathways given in random order. The three treatment pathways were:

1. A-P (i.e. first-line amitriptyline, second-line pregabalin)

2. D-P (i.e. first-line duloxetine, second-line pregabalin)

3. P-A (i.e. first-line pregabalin, second-line amitriptyline).

Members of the research teams at participating sites were granted access to the SCRAM system with individual usernames and passwords. These members of staff were responsible for performing the randomisation process once eligibility had been confirmed by the local investigator. After the randomisation was completed, the pharmacy department was informed that a new participant had been randomised. A member of the pharmacy team then accessed the SCRAM system to obtain the unblinded treatment allocation for the participant to allow dispensing. Pharmacy staff were assigned a different level of access to SCRAM to ensure that they were the only members of the local site team with access to the treatment allocation information.

Interventions

Dose titration

Participants were titrated to a maximum tolerated dose level on starting each new treatment. The schedule for dose escalation was the same in each pathway (Figure 2).

FIGURE 2.

Dosing and titration schedule for treatment pathways. Each pathway had two treatment phases, each with a 2-week initial titration period towards maximum tolerated dose. Participants continued on maximum tolerated maintenance dose of the drug from the first treatment phase for the duration of the second treatment phase. For patients with an eGFR of ≤ 60 ml/minute, the maximum pregabalin dose was 300 mg/day.

When a new treatment was started, all participants started at dose level 1 and the dose was escalated slowly, one dose level at a time, towards a maximum tolerated dose or maximum permitted dose, whichever was reached first (see Table 1). Dose titration decisions were based on treatment response (i.e. 24-hour pain NRS score), side effect profile and participant preference. Dose titrations were usually made during the first 2 weeks of a new treatment; however, investigators were permitted to make dose changes at any time if deemed necessary. At weekly intervals, the site research nurse evaluated the participant’s response to treatment and AEs and this information was used to guide dose titration.

Treatment response

Adequate pain relief was defined as a 24-hour pain NRS score of ≤ 3 for the purposes of dose titration decisions. Participants who experienced adequate pain relief at dose levels 1 or 2 did not have their dose escalated further.

Adverse events

Participants were asked to report all side effects. The local study team graded the side effects as mild, moderate or severe. The participant was asked to rate whether the side effects were tolerable or intolerable. If a side effect was rated as ‘tolerable’ and was non-severe, dose escalation was continued as indicated by the pain score assessment. However, sites were advised that if a patient was experiencing tolerable non-severe side effects, then it was also acceptable to maintain the current dose for a further week to allow side effects to improve before increasing the dose further. This decision was made by the local site team.

If side effects were severe or were rated as ‘intolerable’, then investigators considered reducing the dose by one dose level or discontinuing the medication based on the overall condition of the participant.

Participant preference

Participant preference was taken into account, where possible, when making dose titration decisions. However, the dose was not increased based on participant preference alone (i.e. the dose was increased only if the participant expressed a preference for an increase in dose and if this was indicated based on treatment response and side effect profile).

Treatment phases

Each treatment pathway was split into two treatment phases, as shown in Figure 3.

FIGURE 3.

Two treatment phases per pathway.

First treatment phase

During the first treatment phase, participants received monotherapy with the first-line treatment in the pathway. This lasted for a total of 6 weeks.

Responder/non-responder assessment

At the end of the first treatment phase, a decision was made either to continue on monotherapy or to start combination therapy with the addition of the second-line treatment in the pathway. This decision was based on the 7-day average pain NRS score during the week preceding the week 6 study visit. Participants were divided into ‘responders’ (with a pain score of ≤ 3 points) and ‘non-responders’ (with a pain score of > 3 points). Responders continued on monotherapy and non-responders commenced combination therapy.

Second treatment phase

The second treatment phase lasted for a total of 10 weeks. Responders continued on first-line treatment as a monotherapy for the remainder of the pathway. Non-responders commenced combination therapy, with the addition of the second-line treatment in the pathway, for 10 weeks.

Blinding and masking

The study was double-blinded, whereby participants and the local research team were blinded to treatment allocation, with the exception of the site pharmacist who was unblinded. Blinding was maintained with over-encapsulation and matching placebos. As the study drugs have different dosing schedules (e.g. amitriptyline is given once per day, whereas pregabalin is given twice per day), the placebos were used to ensure that the dosing schedule was identical across the three pathways, with dosing twice per day on all treatments. The IMP bottles were supplied with a tear-off label, which the centre’s pharmacist removed prior to dispensing to the participants. Participants and sites were aware of whether monotherapy or combination therapy had been prescribed and of the dose level. Unblinding was considered only in the event of a medical emergency where knowledge of the participant’s treatment allocation would change the clinical management. All participants were unblinded at the end of the study, when the final statistical report was completed.

Data collection and management

Data management was provided by the University of Sheffield CTRU who adhere to their own standard operating procedures relating to all aspects of data management, including data protection and archiving.

Participant confidentiality was respected at all times and the principles of the UK Data Protection Act40 were followed. All participants were assigned a unique study identification number at screening that linked all of the clinical information held about them on the study database. Data were collected on standardised questionnaires and study-specific case report forms (CRFs) and were entered onto the CTRU’s in-house data management system (Prospect). Access to Prospect was controlled by usernames and encrypted passwords, and a comprehensive privilege management feature was used to ensure that users had access to only the minimum number of data required to complete their tasks. This was used to restrict access to personal identifiable data. After data had been entered onto the database, electronic validation rules were applied on a regular basis and discrepancies were tracked and resolved. All entries and corrections were logged, with the person, date and time captured within the electronic audit trail.

Regular site monitoring visits occurred throughout the study and additional visits were undertaken where required. At these visits, the monitor reviewed activity to verify that the data were authentic, accurate and complete. Accurate and reliable data collection was assured by verification and cross-check of the CRFs against investigator’s records (i.e. source document verification). The study monitor contacted and visited sites regularly to inspect CRFs throughout the study to verify adherence to the protocol and the completeness, consistency and accuracy of the data being entered on the CRFs. Monitoring visits also included a pharmacy visit to review processes, documentation and accountability of study drugs. CTRU staff reviewed entered data for possible errors and missing data points. A central review of consent forms was also completed, and sites were requested to post consent forms to CTRU on an ongoing basis. CTRU reviewed pharmacy dispensing logs for some patients centrally.

Study records will be stored for 25 years after the completion of the study before being destroyed.

Outcome measures

The study evaluated the superiority of at least one pathway in reducing the 7-day average 24-hour pain in patients with diabetic neuropathy.

Economic evaluation

A within-trial economic evaluation was completed as part of the study to understand the relative cost-effectiveness of the three treatment pathways.

Data collection tools

A pro forma of each of the forms was available to be used as source documents if needed. These forms were provided to each site electronically, along with a paper copy of each form for reference.

Ancillary substudies

Participants were given the opportunity to consent to blood sample collection for future research. This aspect of the study was optional, and participants could take part in the main study without consenting to the blood sample collection. Samples were obtained at the same time as other study blood samples (i.e. week –2 or week 16 of each pathway) and shipped directly to the central labs via Royal Mail (Royal Mail Group plc, London, UK).

Patient and public involvement

Patient and public involvement (PPI) representatives have been involved throughout the study, including involvement in the initial study design, as well as implementation and oversight. The Diabetes PPI Panel at Sheffield Teaching Hospitals NHS Foundation Trust reviewed the study at the proposal stage. The PPI representatives were supportive of the proposal, including the study design, and they contributed to the choice of end points for the study. The panel was later involved in the development of the patient information sheet, consent form and study medication diary, helping to ensure that the study documents were accessible for potential participants. The Trial Steering Committee (TSC) included a PPI representative who provided ongoing input into the oversight of the study. PPI representation on the TSC ensured that the patient perspective was considered throughout the trial, including in decision-making regarding protocol amendments and trial recruitment strategies.

Trial management and oversight

Changes to the protocol

All protocol amendments are listed in Appendix 3. A summary of the key changes is provided below.

Statistical methods

Health economic methods

A within-trial cost–utility analysis was conducted alongside the clinical study. The cost–utility analysis estimated the mean differences in costs, QALYs and the incremental cost-effectiveness ratio (ICER) over 16 weeks for each treatment pathway. The cost–utility analysis was conducted in line with the NICE Guide to the Methods of Technology Appraisal62 and is in line with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. 63 The analysis is presented from an NHS and Personal Social Services perspective.

Participant recruitment

Figures 4 and 5 detail the patient flow through the study by treatment (i.e. A-P, D-P and P-A) and by chronological treatment pathway (first, second and third). Participating sites collected pre-screening data on all patients who the site had been in contact with regarding the study. Between 2 October 2017 and 31 July 2019, 1004 patients were identified as being potentially eligible for the trial across 18 secondary care hospital centres (a further three centres were activated to recruitment, but did not identify any potential participants). Of these patients, 426 were ineligible. The main reasons for ineligibility at this stage were not having neuropathic pain (n = 202), contraindications for study medications (n = 42), having other painful medical conditions (n = 39) and use of prohibited concomitant treatment (n = 28). A further 314 patients were not interested or unable to continue into the study, with the main reasons being that they were unable or unwilling to attend all study visits (n = 146) or were not wanting to come off current treatment (n = 76). Twelve patients did not continue for other reasons.

FIGURE 4.

Patient disposition and study flow chart. a, Switch to second-line monotherapy before week 6; and b, includes switches to second-line monotherapy after week 6.

FIGURE 5.

Patient disposition and study flow chart by chronological treatment pathway.

Between 2 October 2017 and 31 July 2019, 252 patients attended the consent visit at week –2 across 17 trial centres, and 222 of these patients provided informed consent. Of those patients who consented, 40 discontinued from the trial before randomisation and a further 42 were ineligible because of unconfirmed or low levels of neuropathic pain (n = 37) or clinically significant arrhythmia (n = 5). One hundred and forty patients proceeded to be randomised at week 0 across 13 sites. Ten patients were excluded following randomisation and within the first treatment pathway. Six patients provided no post-baseline data (three withdrew citing the trial burden, two were lost to follow-up and one developed a significant comorbidity) and four were randomised in error.

A total of 53 patients withdrew from the study before completing all three treatment pathways. The majority (n = 33) of withdrawals came in the first pathway, with a further 13 withdrawals in pathway 2 and seven withdrawals in pathway 3. The numbers of patients starting first, second and third pathways were 130, 97 and 84, respectively, and the numbers of patients contributing 7-day pain scores at week 16 were 105, 85 and 74, respectively.

Recruitment was originally expected to be completed within 12 months by eight trial centres. Owing to slow recruitment rates, the total number of centres was increased to 21 and a number of changes were made to the eligibility criteria and study processes to improve recruitment (see Chapter 2, Changes to the protocol). In addition, assistance was provided to participating centres via regular teleconferences, recruitment packs and one-to-one discussions with the research fellow based at the lead site in Sheffield.

Protocol non-compliances

A total of 146 (major, n = 73; minor, n = 73) protocol non-compliances were reported during the trial and no serious breaches were reported. Five participants were ineligible and were withdrawn from the trial during the first treatment pathway. One participant did not contribute primary outcome data as a result of a good clinical practice non-compliance in the recording of the data at site.

As the study medication was provided in up to eight blinded medication bottles, the dosing schedule for participants was more complicated than in usual care. Thirty-seven cases of participant non-compliance with treatment were reported. These included the participant taking more/less medication than prescribed or taking medication from incorrect bottles.

Fifty-nine non-compliances were reported in relation to trial treatment or procedural issues and this included 22 cases where a patient was prescribed and/or dispensed an incorrect dose of medication. To our knowledge, the errors in treatment doses did not result in any AEs.

Three non-compliances were reported in relation to on-site visits being missed due to COVID-19 restrictions.

Characteristics of trial participants

Trial participants were of similar age to screened patients (median 61.8 years vs. 61.2 years), but fewer females were enrolled (26% vs. 41%).

The full characteristics of the 130 trial participants are presented in Table 5, split according to whether or not the patient completed the three treatment pathways. The majority (82%) of patients had type 2 diabetes, had experienced neuropathic pain for an average of 5 years (median duration 3.4 years, range 4 months to 25 years) and self-rated their pain at 6.6 points out of 10 points (NRS) and 6.1 points out of 10 points (BPI-MSF). Patients more commonly described their pain as relapsing/remitting as opposed to deep or involved (NPSI) and one-third of participants reported having taken each of amitriptyline, pregabalin, duloxetine and gabapentin at some point prior to trial entry.

Trial medication usage

The study treatment use is summarised in Table 6. The uptake of first-line therapy was similar for each arm, with around half of patients remaining on the highest dose at the end of each pathway. Likewise, discontinuation overall was similar across the three arms, but more patients discontinued duloxetine because of AEs or toxicity. The proportion of patients starting second-line therapy was also similar, as were the proportions on the highest dose level at week 16. More participants discontinued or switched from duloxetine during first-line therapy and more participants discontinued intervention during the P-A pathway, but neither was statistically significant.

Numeric Rating Scale pain

None of the pairwise comparisons was statistically significant. At week 16, among participants with outcome data (i.e. complete-case analysis), mean pain in the A-P arm was 0.1 units lower (i.e. better) than in the D-P and P-A arms, but the prespecified clinically important difference of 0.5 units was either excluded from or on the edge of each pairwise CI. For D-P compared with A-P the mean difference was –0.1 (98.3% CI –0.5 to 0.3), for P-A compared with A-P the mean difference was –0.1 (98.3% CI –0.5 to 0.3) and for P-A compared with D-P the mean difference was 0.0 (98.3% CI –0.4 to 0.4) (Table 7). These findings were robust across a range of analyses that assessed missing data under plausible scenarios (Figures 6 and 7), in which the 47 (15%) instances of missing data were imputed by last observation carried forward, multiple imputation or controlled multiple imputation. In all cases, the point effects were within ± 0.1 points.

FIGURE 6.

Pairwise comparisons of NRS pain score at week 6. MI, multiple imputation. LOCF, Last observation carried forward.

FIGURE 7.

Sensitivity analysis of NRS pain score at week 16. MI, multiple imputation. LOCF, Last observation carried forward.

The differences at week 6 were larger among patients in the P-A arm, having greater average pain than patients in the D-P and A-P arms; however, again, none of these differences was statistically significant. For the complete-case scenario, the difference between P-A and A-P was 0.3 (98.3% CI –0.1 to 0.8; p = 0.0492), with similar findings in analyses of imputed data, reflecting the similar levels of ‘for cause’ missing data in the two arms. Nevertheless, none of the arms differed on average by more than 0.4 points in any scenario and none was statistically significant at the predefined alpha = 0.0167 level. In total, there were 12 (4%) instances of missing data, meaning that the impact of missing data was small.

Response to treatment

Treatment response is summarised in Table 8. As noted above, duloxetine was the least well-tolerated monotherapy and had the lowest response rate (27% vs. 30% for amitriptyline and 34% for pregabalin) at week 6, although, again, this comparison was not statistically significant. The overall response rates at week 16 were 46% (A-P), 43% (D-P) and 46% (P-A).

TABLE 8 - Overview of treatment response

Remained on monotherapy with a NRS score of ≤ 3 points at the week 6 visit.

NRS score of ≤ 3 points at the week 16 visit without discontinuation of intervention for AE or poor response.

More than one criteria may apply.

Pathway	Number starting	Response status
		Week 6 (monotherapy)	n (%)	Week 16 (combination)	n (%)
A-P	104	Respondersa	31 (30)	Respondersb	48 (46)
		Non-respondersc	69 (66)	Non-responders	50 (48)
		Stopped first-line therapy	21 (20)	Stopped treatment pathway for AE/poor response	11 (11)
		Started second-line therapy	17 (16)	NRS score > 3 points	41 (39)
		NRS score > 3 points	52 (50)
		Missing	4 (4)	Missing	6 (6)
D-P	100	Respondersa	27 (27)	Respondersb	43 (43)
		Non-respondersc	73 (73)	Non-responders	52 (52)
		Stopped first-line therapy	22 (22)	Stopped treatment pathway for AE/poor response	11 (11)
		Started second-line therapy	21 (21)	NRS score > 3 points	42 (42)
		NRS score > 3 points	57 (57)
		Missing	0	Missing	5 (5)
P-A	107	Respondersa	34 (32)	Respondersb	49 (46)
		Non-respondersc	71 (66)	Non-responders	50 (47)
		Stopped first-line therapy	19 (18)	Stopped treatment pathway for AE/poor response	13 (12)
		Started second-line therapy	16 (15)	NRS score > 3 points	38 (36)
		NRS score > 3 points	55 (51)
		Missing	2 (2)	Missing	8 (7)
Complete case: 7-day average pain, mean (SD) [n]
A-P		3.8 (2.0) [100]		3.3 (1.8) [91]
D-P		3.9 (1.9) [95]		3.3 (1.8) [85]
P-A		4.1 (2.1) [104]		3.3 (1.8) [88]

Figure 8 shows the trajectory of average self-reported pain by randomised sequence, ranging over the 52 weeks of study (pain scores were not routinely completed for the washout periods and have not been included). Self-rated pain did not return to pre-randomisation levels in the washout periods between pathways 1 and 2 or between pathways 2 and 3. This tempers the conclusions that can be made for the change from baseline outcomes (i.e. 30% or 50% reductions), but the inclusion of period number in the statistical model meant that between-arm comparisons remained valid.

FIGURE 8.

Self-reported NRS pain by time in study.

Figure 9 shows the trajectory of average NRS score by time within each pathway. The three curves largely overlap throughout the 16 weeks, suggesting that the arms have equivalent efficacy both in the monotherapy phase (i.e. weeks 0–6) and thereafter. Pain scores continued to decrease after week 6 when combination therapy was offered to participants (mean score: week 16 3.3 vs. week 6 3.9), although qualitatively the scores appeared to plateau around week 12.

FIGURE 9.

Self-reported NRS pain by treatment pathway.

Figure 10 shows the same data as the previous figure, but separately for patients remaining on monotherapy or starting combination therapy on or after week 6. By definition, patients starting combination therapy had higher NRS scores (i.e. worse pain control) at week 6, with average pain levels appearing to plateau in the weeks prior to this. Thereafter, the curves began to converge, with a further mean drop of 1 NRS point among patients on combination therapy (again plateauing over the last weeks of the pathway) compared with 0.2 points among patients on monotherapy (Table 9). This suggests a benefit of combination therapy among patients who had less response to monotherapy alone.

FIGURE 10.

Self-reported NRS pain by use of combination therapy and treatment pathway.

TABLE 9 - Change from week 6 to week 16 by treatment pathway and use of combination therapy

Figures are mean (98.3% CI) change from week 6 to week 16.

Outcome	Treatment pathway			All arms
	A-P	D-P	P-A
Started combination therapy	0.9 (0.4 to 1.4)	0.9 (0.4 to 1.5)	1.1 (0.5 to 1.6)	1.0 (0.6 to 1.3)
Remained on monotherapy	0.1 (–0.4 to 0.6)	0.2 (–0.3 to 0.7)	0.3 (–0.2 to 0.8)	0.2 (–0.1 to 0.5)
Overall change by arm	0.5 (0.1 to 0.8)	0.5 (0.2 to 0.9)	0.7 (0.3 to 1.0)	0.6 (0.3 to 0.8)

Subgroup analyses

Further exploratory work looked at whether or not there were subgroups of patients who responded better to some therapies. Figure 11 depicts patient response to monotherapy at week 6 via a Venn diagram. Although most patients responded either to none (n = 37) or all (n = 13) of the therapies, 30 of the 80 patients who provided data had different responses to the treatments.

FIGURE 11.

Response to monotherapy among patients starting all three pathways. Response defined as a NRS score of ≤ 3 points and no informative treatment withdrawal. Four patients provided no data to at least one pathway.

The results of the subgroup analyses are presented in Appendix 4, Figure 16. Pain was, on average, higher among younger (< 60 years) patients than among the older (≥ 60 years) patients, but the three pathways showed similar efficacy within each of the two subgroups (see Figure 16a). A similar theme was apparent for baseline pain score, with week 16 pain being higher among patients with more severe pain (i.e. a NRS score of ≥ 7 points) but no interaction with treatment (see Figure 16b).

The average week 16 NRS scores were similar across the three pain phenotypes (see Figure 16c). There were, however, some interactions among the individual NPSI components, with a suggestion that D-P was less suited to participants with higher NPSI scores.

There was some evidence of an interaction between treatment and baseline mood. The A-P pathway was notably worse at 16 weeks for patients with high levels of anxiety or depression. Patients with moderate anxiety or depression (scores below 15) had similar responses regardless of treatment arm (see Figure 16j and k).

Pain was also investigated in relation to whether or not the patient had previously used the three study drugs (i.e. amitriptyline, duloxetine and pregabalin) or any opioids (see Figure 16l–o). For all four drug options, patients who had previously been prescribed drugs reported higher pain scores than patients who had not, most notably opioids. Nevertheless, the difference between treatment arms appeared unaffected by previous medication use.

Finally, pain responses during the period of the UK lockdown due to COVID-19 (defined as on/after 20 March 2020) were similar to those measured prior to lockdown, meaning that the treatment comparisons were similar both within lockdown and outside lockdown (see Figure 16p and q). There was no apparent change in weekly NRS scores following imposition of lockdown measures, or any other temporal changes.

Tolerability

Tolerability (rated on a 0–10 NRS, with 10 being least tolerable) was similar between arms at weeks 6 and 16. Scores at weeks 6 and 16 were also similar, suggesting no perceived worsening in side effects with the introduction of combination therapy. In fact, self-reported tolerability was slightly better at week 16 than in week 6, albeit not statistically significantly so (Table 10).

Quality of life

General health (assessed by SF-36), health utility (assessed by EQ-5D-5L) and anxiety/depression (assessed by HADS) are shown in Table 11. Self-reported QoL was similar across the three arms and no consistent patterns were observed among the QoL inventories. Some of the comparisons were statistically significant. After 6 weeks of treatment, duloxetine was associated with worse limitations due to physical health compared with amitriptyline and pregabalin, but was preferable with regard to general health, as assessed via SF-36 (Figure 12) and EQ-5D-5L. All differences were modest in clinical or psychometric terms. No statistically or clinically significant differences were found at 16 weeks.

FIGURE 12.

Short Form questionnaire-36 items domains. Graphs depict the model-based mean and CI for each treatment arm for each of the nine domains at week 16. Higher scores indicate better QoL.

Other pain inventories and insomnia

As with the NRS, the NPSI and BPI-MSF were largely similar across arms at 6 and 16 weeks (Table 12). In general, the D-P arm had the highest pain scores at week 16, with the P-A arm having the lowest, but none of the comparisons was statistically significant. By contrast, week 6 pain scores tended to be higher in the P-A arm, with two BPI-MSF scores (worst pain over 24 hours and overall pain severity) being significantly lower in the A-P treatment pathway.

Self-reported insomnia (via the ISI) is summarised in Table 13. Patients rated their insomnia worse in the D-P arm than in the A-P arm, both at week 6 (mean difference = 1.5, 98.3% CI 0.0 to 3.1; p = 0.016) and at week 16 (mean difference = 1.5, 98.3% CI 0.1 to 3.0; p = 0.010).

Patient impression of change and treatment preference

Finally, participants were asked to complete a global impression of change (using the PGIC) at the end of each pathway and their preferred treatment if they had completed the three pathways (Table 14). The treatments were rated positively among this group, with 44%, 43% and 49% of patients reporting ‘much improved’ or ‘very much improved’ for A-P, D-P and P-A, respectively (Kruskal–Wallis test p = 0.70).

On reaching the end of the study, participants were asked to rate their preferred treatment of the study. The most popular choice was P-A (43%), followed by D-P (33%) and A-P (24%), although this comparison was not statistically significant (p = 0.266).

Adverse events

Adverse events are summarised by pathway in Table 15. Fatigue was the most commonly reported AE and was similarly prevalent in each pathway. The most notable difference was in the incidence of dry mouth, which was associated with amitriptyline (A-P, 32%; P-A, 17%; D-P, 8%) (p < 0.001). Dizziness was more common in patients in the P-A arm (24%) than in patients in the A-P (12%) and D-P (16%) arms, and nausea was highest (23%) in the D-P arm (vs. 5% in the A-P arm and 7% in the P-A arm; p = 0.001).

Table 16 shows AEs further split by the time they occurred (i.e. before or after 6 weeks) and SAEs are tabulated in Table 17. One SUSAR occurred [one participant experienced an atrioventricular heart block (Mobitz II) in the P-A arm 11 weeks into the first treatment pathway and while on amitriptyline, having switched from pregabalin at the week 6 visit].

The remaining tables (Tables 18–20) focus on AEs of moderate or severe intensity that are related to one or both study medications. In total, 97 such events occurred, affecting 19% of patients in the A-P arm, 22% of patients in the D-P arm and 21% of patients in the P-A arm (p = 0.719) (see Table 18). A post hoc analysis looked at days affected by moderate or severe related AEs (see Table 19) while in study follow-up, which for the majority of patients was zero but for the groups as a whole resulted in 84, 69 and 73 days per 1000 days of follow-up in the A-P, D-P and P-A arms, respectively (p = 0.858). Most events started during monotherapy but continued to affect patients beyond week 6, by which point combination therapy may have started. The mean days affected for each category is displayed visually in Figure 13 and in Table 20. The AEs with the longest average person-day impacts were dry mouth in the A-P arm (191 days/1000 days of follow-up) and fatigue in all arms (109 days/1000 days of follow-up).

FIGURE 13.

Days impacted by adverse effects.

Quality of life and quality-adjusted life-years

Table 21 presents EQ-5D utility values at baseline and at 6 and 16 weeks for the three treatment pathways. QALYs were similar for the three groups and equate to approximately 55 days or just under 2 months over a 16-week period.

Table 22 provides a breakdown of EQ-5D-5L responses for each of the five domains of the EQ-5D-5L for participants for whom QALYs were generated. At baseline, no one indicated that they had no pain or discomfort, but this improved at 6 and 16 weeks for all three pathways. Similarly, the proportion of patients with no problems with mobility, usual activities and anxiety or depression also increased over time.

Resource use

The most commonly accessed resources were prescription services, podiatry, GPs, practice nurses and outpatient appointments (Table 23). For those attending accident and emergency, patients could attend between one and four times per period. Hospitalisation duration ranged from one to eight nights, and those patients who attended outpatient appointments could attend up to 12 times per period.

Table 24 presents a summary of resource use costs for each pathway. Costs were similar across the three pathways, with treatment costs being cheaper for A-P (mean £1424) and slightly more expensive for P-A (mean £1448) and D-P (mean £1452). Similarities were also observed for overall costs, with P-A, on average, having the lowest cost (mean £1942), with the average costs for A-P (mean £2012) and D-P (mean £2032) being slightly higher, but similar.

Order of treatment effect

Regression models were fitted to both costs and QALYs to examine the effect of order of receiving treatment pathways A-P, D-P and P-A. Table 25 presents the results with 95% bootstrap CIs for the order effect compared with receiving treatments in the first time period. The overall effect of order on costs and QALYs was not significant for the three treatment pathways, although it did approach statistical significance for the A-P pathway, with patients receiving A-P in the third time period more likely to have lower costs than patients receiving A-P in the first time period.

Cost-effectiveness analysis

Table 26 presents a summary of the costs and QALYs over 16 weeks for each of the treatment pathways, as well as the pairwise incremental costs, QALYs and cost per QALY gained. Note that participants were eligible to receive all three treatment pathways. However, participants may drop out of the study before receiving all three pathways. Therefore, 67 participants received A-P and D-P, 67 participants received A-P and P-A and 73 participants received D-P and P-A. The incremental QALY gain is small and is uncertain when comparing A-P with D-P and A-P with P-A. However, there is a gain for those on the D-P pathway, equating to approximately 2.5 days when comparing D-P with P-A. The incremental cost gain was not significant for any comparison and ranged between a mean of –£113 for A-P compared with D-P and a mean of £154 for A-P compared with P-A. Figure 14 shows the cost-effectiveness planes for each pathway comparison. On average, D-P is more costly and less effective than A-P, with 57% of points being in the south-west quadrant of the cost-effectiveness plane (mean ICER £7026). A-P and D-P were, on average, more costly but more effective than P-A, with the majority of points being in the north-east quadrant of the cost-effectiveness plane (A-P vs. P-A mean ICER £7441, 79% in north-east quadrant; D-P vs. P-A mean ICER £94,157, 91% points in the north-east quadrant, respectively) (Figure 15). For all comparisons, it is important to note that they are based on a small QALY gain and a small difference in costs between the two treatment pathways.

FIGURE 14.

Incremental cost-effectiveness plane. (a) A-P vs. D-P; (b) A-P vs. P-A; and (c) D-P vs. P-A.

FIGURE 15.

Cost-effectiveness acceptability curve. (a) A-P vs. D-P; (b) A-P vs. P-A; and (c) D-P vs. P-A.

Sensitivity analysis

Non-pairwise comparisons of the three treatment pathways gave ICERs of £4000 for A-P compared with D-P (with D-P on average being more costly but more effective), –£700,000 for A-P compared with P-A (with P-A being less costly and more effective) and £18,000 for D-P compared with P-A (with P-A being less costly and less effective). The incremental QALY difference is very small and uncertain, which is reflected in the difference in the ICERs between pairwise and non-pairwise comparisons.

Main findings

The OPTION-DM trial showed that all three treatment pathways (i.e. A-P, D-P and P-A) were equally effective in reducing neuropathic pain intensity, significantly reducing the baseline NRS score from a baseline mean of 6.6 (SD 1.5) points to an average of 3.3 (SD 1.8) points at 16 weeks. There were no differences between the treatment pathways, as the effects observed were not different statistically or clinically different between the pathways, with the CIs for the primary end point (i.e. pain at week 16) having the prespecified difference only at their very edge.

As the three treatment options produced similar pain control, it might be important to consider other outcomes when deciding which treatment to recommend; however, no one treatment was uniformly preferable across the end points we assessed.

The P-A pathway led to the fewest discontinuations on monotherapy due to AEs (p = 0.031) and numerically was the most preferred pathway (A-P, 24%; D-P, 33%; P-A, 43%; p = 0.27) at the end of the trial. This is consistent with the American Academy of Neurology recommendations, which give only pregabalin level A evidence, mainly because completion rates in pregabalin trials were more than 80%. 79 The P-A pathway also gave the best pain relief for higher levels of baseline depression (p = 0.011) and both the P-A and D-P pathways provided better pain relief than the A-P pathway for higher levels of baseline anxiety (p = 0.016).

The trial explored a number of secondary end points. The head-to-head trial of maximum tolerated doses of amitriptyline, duloxetine and pregabalin showed similar efficacies for all three monotherapies at the end of 6 weeks, although there were fewer discontinuations due to treatment-emergent AEs with pregabalin. However, only in one-third of patients did monotherapy achieve mild pain (i.e. ‘responders’, with a NRS score of ≤ 3). Similarly, monotherapy achieved 50% pain relief in around 40% of patients. Most patients (‘non-responders’) required combination treatment, which resulted in a 0.6-point further improvement in NRS score and 18% and 14% increases in the achievement of a NRS score of ≤ 3 points and 50% pain relief, respectively. In a crossover trial, Gilron et al. 57 studied 56 patients with neuropathic pain (40 patients with DPNP) treated to maximum tolerated doses of gabapentin, nortriptyline and their combination over 1-month treatment periods. They found that combination treatment was more efficacious than either drug alone. Another crossover trial80 (n = 73), of 5-week treatment periods, compared the combination of imipramine and pregabalin at moderate doses with either treatment on its own in painful polyneuropathy. The study found that combination treatment was more efficacious in relieving neuropathic pain than either drug on its own, but resulted in higher rates of side effects. Despite these results, currently, a number of international bodies do not recommend combination treatment for DPNP because of ‘insufficient evidence’. 81–83 Although the OPTION-DM trial was not designed as a comparison of monotherapy and combination treatment, the data make a compelling case for the recommendation of combination treatment of first-line drugs for DPNP patients with suboptimal response to a monotherapy.

Despite massive variations in the cost and availability of amitriptyline, duloxetine and pregabalin in many countries, it is reassuring that all three drugs are equally efficacious in relieving pain. Furthermore, all monotherapies resulted in a substantial improvement of QoL domains, sleep and measures of mood from baseline. However, amitriptyline was significantly better than duloxetine in improving physical functioning and sleep, and pregabalin was superior to duloxetine in improving role limitation due to physical health. Treatment-emergent AEs were predictable for the monotherapies, although there were no significant differences in their overall frequency and severity. This may, in part, be due to the use of maximum tolerated doses rather than a fixed treatment regime. There were also no significant differences in the frequency of SAEs. However, compared with some previous studies, combination treatment with maximum tolerated doses was well tolerated, with few treatment-emergent AEs, except for larger numbers of patients reporting diarrhoea and dry mouth in the A-P pathway.

Health economics

To the best of our knowledge, this study is the first to present the results of a head-to-head comparison of current medications and their combinations in an economic evaluation over a 16-week period. QALYs were similar over the study time period, with an average difference in costs ranging from –£113 to £154 across the three comparisons. Ninety-five per cent bootstrap CIs around costs and QALYs demonstrated the uncertainty in results. Furthermore, the study showed that greater costs are borne by the patients and their carers rather than the NHS.

Wu et al. 32 examined the cost-effectiveness of duloxetine compared with usual care over a 52-week period. Wu et al. 32 looked at three perspectives and found incremental costs slightly higher than those for our study [i.e. direct (closest possible to NHS) US$1600 (£1194); employment and direct US$2196 (£1639) and societal, direct and employment US$2754 (£2056)]. However, in addition to looking at single rather than combination therapy, the time period is longer in the Wu et al. 32 study and the health-care system is different in the USA and, therefore, caution should be given when comparing these results with those from the OPTION-DM trial.

Two further studies33,34 looked at duloxetine in decision-analytic models. O’Connor et al. 34 presents the cost per QALY of duloxetine compared with desipramine at US$47,700 (or £35,609). This is higher than our average QALY for A-P compared with D-P (£7026) and lower than the average QALY for D-P compared with P-A (£94,157), although it should be noted, again, that this is not a combination therapy study and the time period is shorter and so not comparable. It should also be noted that the O’Connor et al. 34 results were sensitive to obtaining pain relief. Beard et al. 33 also fitted a decision-analytic model and noted a saving of £77,071 for every 1000 patients treated in 2007 or £109,246 per 1000 patients in 2019.

Finally, de Salas-Cansado et al. 35 compared pregabalin with usual care from a Spanish NHS and societal perspective over a 23-week period. The costs per QALY were higher than those for our study [i.e. €5302 (£4426) societal and €14,381 Spanish NHS (£12,005)].

Also worth noting is that the utility values for our sample do appear to be low in comparison with those for the general diabetes population. Table 3 presented mean utility values for the EQ-5D at baseline and at 6 and 16 weeks, and these ranged between 0.408 and 0.551. Collado Mateo et al. 84 present normative values for a Spanish diabetes population by age and sex. The mean EQ-5D values for people aged 60–69 years (the most comparable age band to our population mean of 61.8 years) were 0.860 for males and 0.745 for females, respectively. The authors used the Spanish crosswalk rather than UK crosswalk to obtain utilities for the EQ-5D, but other studies also suggest higher utility values. For example, Wang et al. 85 report a mean utility of 0.720 for patients in Singapore with type 2 diabetes mellitus. Likewise, in a Chinese study, Pan et al. 86 report a mean value of 0.862 for patients with type 2 diabetes mellitus and a mean of 0.815 if the patients also had neuropathy.

Strengths and weaknesses of the research

To the best of our knowledge, this was the first randomised double-blind comparator trial of neuropathic pain treatment pathways. Although head-to-head trials of individual monotherapies and combination treatments could be designed, investigating treatment pathways as a whole was felt most efficient and applicable to current clinical practice. This is because most patients are started on a monotherapy and will require a second agent to be added in combination within a few months. Therefore, the OPTION-DM trial reflected current practice, allowing the outcomes of this study to be readily generalisable. Recruitment from a wide array of sites, including primary and secondary care, further strengthens the generalisability of the study.

The initial prespecified number of participants was not recruited, and this could be taken as a limitation of the study. Early monitoring of the fidelity of recruitment revealed that recruitment for this demanding trial was challenging. Rather than compromise the integrity of the trial, and with the approval of the independent TSC and head of the Health Technology Assessment, the trial continued to a fixed time point when an adequate sample size had been achieved to detect a difference of at least 1 NRS point. The onset of the COVID-19 pandemic further affected follow-up, with some participants having a curtailed follow-up in the final pathway. A strength of the OPTION-DM trial was that, although the trial was curtailed in terms of recruitment, to the best of our knowledge, it is still the longest and largest crossover combination trial. Given the results, and that a 0.5-point NRS difference was at the very edge of plausible difference between the treatment arms, even a significantly larger sample size would probably not have altered study outcomes or conclusions.

The lack of a placebo arm can also be taken as a limitation of the study. However, given the existing wealth of evidence from previous placebo-controlled trials and the advice from our PPI panel, we decided against a placebo control, as including a placebo control would have made the trial longer, more complicated (i.e. a four-way crossover trial) and it would not have been ethically justifiable to leave participants on placebo alone for 17 weeks. The number of dropouts within the 1–2 weeks prior to randomisation in this trial suggest that such a trial is not feasible. The lack of a placebo arm means that we cannot attribute the change from baseline solely to the introduction of treatment, as some improvement may be due to regression to the mean. Nonetheless, previous trials14–22 have demonstrated far smaller changes in participants treated with placebo, and it is reasonable to assume that most of the improvement is due to therapy.

The EQ-5D was captured prior to treatment pathway 1, but not prior to treatment pathways 2 and 3, and was captured for each treatment pathway at 6 and 16 weeks. It may be that measuring HRQoL more frequently would more likely capture any disutilities associated with AEs, and any future study should consider this. The economic analysis reports the within-trial results over 16 weeks, and this is in line with other published economic evaluations,31,32 although future studies could consider modelling the cost-effectiveness over a longer time frame.

There are two further limitations of the economic evaluation. First, the use of a questionnaire to capture resource use means that resource use is self-reported and could be subject to recall issues, thereby potentially underestimating the overall cost of each treatment pathway. The capturing of resource use information from routine sources could be considered in future studies. Second, the crossover nature of this study lent itself to a pairwise comparison of the alternative treatment pathways. This pairwise comparison was varied in a sensitivity analysis, which, owing to the small difference in costs and QALY, meant that the results remained uncertain.

Evidence in the context of other existing research

The OPTION-DM trial was an efficiently designed head-to-head crossover trial,2 with each patient undergoing all three pathways over 50 weeks, making it, to the best of our knowledge, the longest blinded neuropathic pain trial. The durations of monotherapy and combination treatment were long enough to assess full treatment effects. 37 Previous combination trials mainly used fixed-dose titration regimens regardless of treatment response. 31,80 This does not reflect clinical practice and often resulted in high dropout rates. 31 The present trial employed a flexible dosing regimen to achieve maximum tolerated doses, based on individual responses. Moreover, all previous DPNP multiperiod crossover trials were smaller. 25–27 In addition, other studies included neuropathic pain conditions other than DPNP. 29,57,80 Finally, most previous trials did not use combinations of current first-line drugs. 29,57,80 The OPTION-DM trial tried to obtain robust data from current first-line drugs, as, based on the trajectory of new drug developments for DPNP over the past 25 years, the emergence and use of revolutionary new drugs that are considerably more efficacious than current ones seemed unlikely over the foreseeable future.

Implications for practice and policy

The OPTION-DM trial has demonstrated that all three treatment pathways and monotherapies are equally efficacious. Although most international painful diabetic neuropathy management guidelines, including the one by NICE (CG96, updated in 2021),82 place the monotherapies as first-line agents, based on indirect comparisons of the treatments’ efficacy, this is, to the best of our knowledge, the first time that an adequately designed head-to-head comparator trial has been undertaken, and it confirmed that the treatments are of equivalent efficacy. The OPTION-DM trial will hopefully reduce the ambiguity of indirect comparisons that, for example, led the French panel of experts to recommend pregabalin as a second-line agent. 87

Combination treatment is currently not recommended by international guidelines because of insufficient evidence. 81–83 NICE guidance,82 which was updated in 2021, recommends switching to a different treatment rather than combination treatment. In this trial, only one-third of patients saw a reduction in pain to ‘mild’ as quantified as a NRS score of ≤ 3 points (‘responders’). Similarly, monotherapy achieved 50% pain relief in around 40% of patients. Many patients (‘non-responders’) required combination treatment that resulted in a further mean improvement of 1 point on the NRS and an additional 18% and 14% increase in the achievement of NRS score of ≤ 3 points and 50% pain relief, respectively. Although the OPTION-DM trial was not designed as a comparison of monotherapy and combination treatment, the data make a compelling case for the recommendation of combination treatment of first-line drugs for DPNP patients with suboptimal response to a monotherapy, particularly as combination treatment was very well tolerated.

In clinical practice, patients are sometimes prescribed very high doses of amitriptyline (up to 150 mg/day) and, therefore, it is no great wonder that so many patients experience unwanted side effects. The OPTION-DM trial has shown that titration to 60 mg per day can be effective. The OPTION-DM trial also found that the mean dose per day (% on maximum dose) of amitriptyline, duloxetine and pregabalin at week 6 was 60 mg (59%), 82 mg (53%) and 396 mg (56%), respectively. For patients on combination treatments A-P, D-P and P-A the mean dose per day (% on maximum dose) of add-on drug at week 16 was 365 mg (47%), 407 mg (55%) and 55 mg (47%), respectively. These data show that only around half of patients will tolerate maximum doses of these drugs, and this is in the context of a clinical trial that excluded patients with major comorbidities. A key message from the OPTION-DM trial is that drugs need to be titrated gradually, over at least 2 weeks and, in some patients (for example the elderly and those with comorbidities) even more slowly, factoring in the side effect profile and the severity of side effects, as well as efficacy.

The data from OPTION-DM trial are powerful. The OPTION-DM trial was, to the best of our knowledge, the longest blinded neuropathic pain trial to date. Unlike previous combination treatment crossover trials,37 the durations of monotherapy and combination treatments were long enough to assess full treatment effects. Moreover, previous combination trials31,80 mainly used fixed-dose titration regimens regardless of treatment response, which does not reflect clinical practice and resulted in high dropout rates. The OPTION-DM trial employed a flexible dosing regimen to achieve maximum tolerated doses, based on individual responses. Moreover, all previous DPNP multiperiod crossover trials25–27 had smaller sample size and other studies29,57,80 included neuropathic pain conditions other than DPNP. In addition, most previous trials did not use combinations of current first-line drugs. Therefore, the robustness of OPTION-DM trial data will probably influence clinical practice, guidelines and commissioners.

Implications for health care

The current NICE guideline (CG173)82 for the management of painful DPNP states:

Offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain.

If initial treatment is not effective or is not tolerated, offer one of the remaining 3 drugs, and consider switching again if the second and third drugs tried are not effective or not tolerated.

© NICE 2020 Neuropathic Pain in Adults: Pharmacological Management in Non-Specialist Settings. 82 Available from www.nice.org.uk/guidance/cg173. All rights reserved. Subject to Notice of rights NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication

The OPTION-DM trial was a pragmatic trial reflecting current best-treatment practice and examined three treatment pathways for painful diabetic neuropathy. In each treatment pathway, patients were initially commenced on monotherapy followed by combination therapy. The results showed significant improvements in pain severity in all three treatment pathways. In addition, the results showed that combination treatment is not only safe but also necessary for a significant proportion of patients to achieve meaningful pain relief (i.e. a NRS pain score of ≤ 3 points).

The most recent NICE CG173 guideline82 recommends that patients switch to a second or third agent if initial/subsequent monotherapy is ineffective. In practice, this often results in poor patient satisfaction and disillusionment, as well as failure to achieve adequate pain relief due to treatment inertia. The results of the OPTION-DM trial suggest that combination treatment may be advocated if inadequate pain relief is achieved with monotherapy. To facilitate this, future pharmacotherapy guidelines for painful diabetic neuropathy should be rationalised into treatment pathways, as the majority of patients end up having combination treatments. Our cost-effectiveness analysis shows that there are no differences between the treatment pathways assessed. Further post hoc analyses are being planned to examine if certain subgroups of patients (e.g. the elderly, patients with mood disorders or clinical pain phenotypes) respond better to a particular treatment pathway.

Recommendations for future research

The OPTION-DM group

Solomon Tesfaye was the chief investigator.

Dinesh Selvarajah was the co-chief investigator.

The following were co-applicants on the grant, contributed to the study design, were members of the TMG and contributed to data interpretation: David Bennett, Oscar Bortolami, Didier Bouhassira, Cindy Cooper, Rajiv Gandhi, Ravikanth Gouni, Michelle Horspool, Martin Johnson, Edward Jude, Steven A Julious, Satyan Rajbhandari, Gerry Rayman, Prashanth Vas and David White.

The following were site PIs and members of the TMG: Syed Haris Ahmed, Uazman Alam, David Bennett, Augustin Brookes, Marion Devers, Frances Game, Ravikanth Gouni, Christian Hariman, Pallavi Hegde, Edward Jude, Deirdre Maguire, Rory McCrimmon, Claire McDougall, David Price, Satyan Rajbhandari, Gerry Rayman, Abd Tahrani, Solomon Tesfaye, Vasileios Tsatlidis and Prashanth Vas.

The following contributed to participant recruitment, treatment delivery and data collection at sites: Quratul-ain Altaf, Samantha Anderson, Maureen Armstrong, Helen Atikins, Olabisi Awogbemila, Gayna Babington, Sarah Beck, Safia Begum, Elizabeth Bell, Dina Bell, Srikanth Bellary, Lyndsay Bibb, Sharron Birch, Hannah Bond, Elaine Brinkworth, Margaret Broome, Jamie Burbage, Charlotte Busby, Caroline Calver, Christine Cassidy, Tanith Changuion, Carolyn Chee, HoYee Cheung, Kamalakkannan Chokkalingham, Wahid Chugtai, Martyn Clark, Lynda Connor, Amanda Cook, Shirley Cooper, Martina Coulding, Joanna Cox, Helen Cross, Jacqueline Currie, Claire Davies, Caroline Davies, Rebecca Denyer, Laura Dinning, Julie Edwards, Branwen Ellison-Handley, Sarah Finbow, Annette Fleet, Kamini Gandhi, Laura Gardiner, Karyna Gibbons, Amanda Gillespie, Louisa Green, Peter Hammond, Gail Hann, Kate Harrington, Melanie Hayman, Stephanie Horler, Liew Huiling, Wanda Ingham, Ahmed Iqbal, Andrew Irwin, Khalid Jadoon, Victor Jardin, Helen Jenner, Jane Jiao, Katherine Jones, Frank Joseph, Joanne Kadziola, Maqsood Khan, Rosemary Kirk, Alistair Lamb, Rebecca Lenagh, Jonathan Lim, Jackie Lindsay, Linda Macliver, Ellen Malcolm, Barbara Martin, Shamiso Masuka, Alexandra McCarrick, Jacqueline McCormick, Carly McDonald, Nicky McRobert, Aye Min, Ahmad Moolla, Nadim Musah, Alison Musgrove, Sunil Nair, Kilimangalam Narayanan, Abida Nazir, Kelly Nicholson, Francis O’Rourke, Pedro Okoh, Matilde Pascal, Helen Permain, Shirley Peta Navein, Kristina Posadas, James Pratt, Tejpal Purewal, Taslima Rabbi, Sutapa Ray, Rustam Rea, Elsa Redfearn, Gillian Reekie, tephanie Ridgeway, Josephine Rosier, Daniel Rowlandson, Efisia Sais, Lorelei Salazar, Sunita Sandhu, Chandbi Sange, Vivienne Savage, Heather Savill, Caroline Scott, Susan Seal, Ruta Segamogaite, Dinesh Selvarajah, Ajmal Shakoor, Sanjeev Sharma, Gordon Sloan, Dawn Spick, Mara Sprengel, Lisa Stewart, Wendy Stoker, Sharon Storton, Kyla Story, Negar Tadayon, Garry Tan, Andreas Themistocleous, Sue Thomson, Viv Thornton-Jones, Nicola Tinker, Victoria Tobin, Kim Turner, Victoria Turner, Tom Vale, Joanne Vere, Janaka Vithanage, Lisa Wadeson, Taryn Ward, Rachel Whitham, Helen Wild, Andrew Williams, Annie Williamson, Jayne Willson, Ann Wilson, Charlene Wong, Noah Yogo and James Young.

The following contributed to pharmacy and IMP management at sites: Wendy Abbott, Fiona Ashworth, Bhavna Badiana, Liz Bedford, Michelle Beecroft, Sarah Bik, Nicola Blain, Sathan Boonyaprapa, Rachel Bower, Helen Bowler, Louise Brannon, Zara Brown, Shona Carson, Tom Carter, Katie Carter, Stuart Chandler, Vicky Chu, Irene Coburn, Amy Cox, Fionnuala Cunningham, Laura Cureton, Tori Donaldson, James Donworth, Samantha Eccles, Sharon Evans, Jordi Evans, Joanna Flanagan, Emma Galloway, Linda Gemmell, Dilbagh Gill, Marie Goldsworthy, Carlos Gonzalez, Alfonso Gonzalez-Blas, Joanne Gordon, Senait Haile, Clair Hammond, Benson Ho, Sheila Hodgson, Alison Hogan, Sam Holloway, Louise Hough, Matthew Howlett, Cath Hughes, Tracy Jackson, Sam Jackson, Carol Jaques, Dom Jimenez, Natalie Johnston, Paul Jones, Kelly Kauldhar, Laura Kirk, Paige Kissane, Caroline Loan, Jennifer Lynch, Helen Lyon, Jill Lyons, Greg Marchant, Steven Marshall, Peter Mason, Heather Michael, Laura Miller, Gaynor Notcheva, Samuel Nyabam, Matthew Quinn, Andrew Reid, Rosalind Roberts, Fiona Ross, Pam Rushworth, Nita Shah, Victoria Shakespeare, Tania Slater, David Sproates, Anita Stevenson, Kashmira Subramanian, Benham Tabrizi, Rebecca Tangney, Paul Taylor, Nichole Thompson, Christopher Waterhouse, Sue Wiles, Andrew Wilkinson and Elaine Wilson.

Erica Wallis was the sponsor representative and provided support on ethics and governance issues.

Rachel Glover, Jennifer Petrie, Katie Sutherland and Lizzie Swaby provided central trial management and monitoring.

Mike Bradburn provided the statistical support.

Tracey Young provided the health economics support.

Amanda Loban, Emily Turton and Simon Waterhouse provided central data management.

Zoe Furniss and Jess Welburn provided central administration.

Trial Steering Committee

Andrew Rice, independent chairperson (Professor of Pain Research, Imperial College London).

Ralf Baron (Professor of Pain Research, University Medical Centre Schleswig-Holstein).

Sarah Brown (Principal Statistician, University of Leeds).

Arthur Durrant (patient representative).

Nanna Finnerup (Professor of Pain Medicine, Aarhus University).

Roger Knaggs (Associate Professor in Clinical Pharmacy Practice, University of Nottingham).

Jane Lewis (Senior Lecturer in Podiatry, Cardiff School of Sport and Healthcare Science).

Data Monitoring and Ethics Committee

Troels Jensen, independent chairperson (Professor of Neurology and of Experimental and Clinical Pain Research, Aarhus University).

Zoe Hoare (Principal Statistician, Bangor University).

Martin Rutter (Professor of Cardiometabolic Medicine, University of Manchester).

Contributions of authors

Solomon Tesfaye (https://orcid.org/0000-0003-1190-1472) (Consultant Endocrinologist and Honorary Professor of Diabetic Medicine) produced the first draft of the report, was a member of the TMG, contributed to the delivery of the trial, was an applicant on the Health Technology Assessment grant, contributed to the study design and was an investigator at a participating site.

Gordon Sloan (https://orcid.org/0000-0001-6164-2662) (Clinical Research Fellow) produced the first draft of the report, was a member of the TMG and contributed to the delivery of the trial.

Jennifer Petrie (https://orcid.org/0000-0001-6150-6724) (Trial Manager) produced the first draft of the report, was a member of the TMG and contributed to the delivery of the trial.

David White (https://orcid.org/0000-0003-2871-7946) (Senior Research Fellow/Portfolio Lead) produced the first draft of the report, was a member of the TMG, contributed to the delivery of the trial, was an applicant on the Health Technology Assessment grant and contributed to the study design.

Mike Bradburn (https://orcid.org/0000-0002-3783-9761) (Senior Statistician) produced the first draft of the report, was a member of the TMG and contributed to the delivery of the trial.

Tracey Young (https://orcid.org/0000-0001-8467-0471) (Health Economist) produced the first draft of the report, was a member of the TMG and contributed to the delivery of the trial.

Satyan Rajbhandari (https://orcid.org/0000-0002-3995-5336) (Consultant Physician and Diabetologist) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Sanjeev Sharma (https://orcid.org/0000-0001-6386-2052) (Consultant, Endocrinology and Diabetes) was an investigator at a participating site and was a member of the TMG.

Gerry Rayman (https://orcid.org/0000-0003-3331-7015) (Consultant Physician, Diabetes and Endocrinology) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Ravikanth Gouni (https://orcid.org/0000-0002-5852-470X) (Consultant, Diabetes and Endocrinology) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Uazman Alam (https://orcid.org/0000-0002-3190-1122) (Senior Clinical Lecturer and Honorary Consultant Physician, Cardiovascular and Metabolic Medicine) was an investigator at a participating site and was a member of the TMG.

Steven A Julious (https://orcid.org/0000-0002-9917-7636) (Professor of Medical Statistics) was an applicant on the Health Technology Assessment grant, contributed to the study design and was a member of the TMG.

Cindy Cooper (https://orcid.org/0000-0002-2995-5447) (Professor of Health Services Research and Clinical Trials) was an applicant on the Health Technology Assessment grant, contributed to the study design and was a member of the TMG.

Amanda Loban (https://orcid.org/0000-0001-7089-1580) (Lead Data Manager) was a member of the TMG and provided central data management.

Katie Sutherland (https://orcid.org/0000-0002-5162-8119) (Research Assistant) was a member of the TMG and contributed to the delivery of the trial.

Rachel Glover (https://orcid.org/0000-0002-2460-3354) (Trial Manager) was a member of the TMG and contributed to the delivery of the trial.

Simon Waterhouse (https://orcid.org/0000-0002-6303-9610) (Data Manager) was a member of the TMG and provided central data management.

Emily Turton (https://orcid.org/0000-0001-5763-9604) (Data Manager) was a member of the TMG and provided central data management.

Michelle Horspool (https://orcid.org/0000-0002-3069-6091) (Research Development Manager) was an applicant on the Health Technology Assessment grant, contributed to the study design and was a member of the TMG.

Rajiv Gandhi (https://orcid.org/0000-0002-2008-2301) (Consultant Diabetologist) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Deirdre Maguire (https://orcid.org/0000-0001-6730-0997) (Consultant in Diabetes and Endocrinology) was an investigator at a participating site and was a member of the TMG.

Edward Jude (https://orcid.org/0000-0002-3186-4122) (Consultant Physician and Honorary Reader in Medicine) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Syed Haris Ahmed (https://orcid.org/0000-0002-7815-2907) (Consultant Physician in Diabetes, Endocrinology and Metabolic Medicine) was an investigator at a participating site and was a member of the TMG.

Prashanth Vas (https://orcid.org/0000-0001-7448-2995) (Consultant Physician) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Christian Hariman (https://orcid.org/0000-0001-6426-5807) (Consultant Physician, Diabetes and Endocrinology) was an investigator at a participating site and was a member of the TMG.

Claire McDougall (https://orcid.org/0000-0003-0138-5267) (Consultant Diabetologist) was an investigator at a participating site and was a member of the TMG.

Marion Devers (https://orcid.org/0000-0003-2605-4093) (Consultant Physician, Diabetes and Endocrinology) was an investigator at a participating site and was a member of the TMG.

Vasileios Tsatlidis (https://orcid.org/0000-0001-9413-5130) (Consultant, Endocrinology and Diabetes) was an investigator at a participating site and was a member of the TMG.

Martin Johnson (https://orcid.org/0000-0002-8398-5436) (Senior Medical Director, hVIVO) was an applicant on the Health Technology Assessment grant, contributed to the study design and was a member of the TMG.

Didier Bouhassira (https://orcid.org/0000-0001-6446-8719) (Director of Research, Inserm) was an applicant on the Health Technology Assessment grant, contributed to the study design and was a member of the TMG.

David L Bennett (https://orcid.org/0000-0002-7996-2696) (Professor of Neurology and Neurobiology) was an applicant on the Health Technology Assessment grant, contributed to the study design, was a member of the TMG and was an investigator at a participating site.

Dinesh Selvarajah (https://orcid.org/0000-0001-7426-1105) (Senior Clinical Lecturer in Diabetes and Honorary Consultant Physician) produced the first draft of the report, was a member of the TMG, contributed to the delivery of the trial, was an applicant on the Health Technology Assessment grant, contributed to the study design and was an investigator at a participating site.

Publications

Selvarajah D, Petrie J, White D, Julious S, Bortolami O, Cooper C, et al. Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial. Trials 2018;19:578. https://doi.org/10.1186/s13063-018-2959

Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, et al. 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;400:680–90.

Data-sharing statement

Requests for patient-level data and statistical code should be made to the corresponding author and will be considered on a case-by-case basis following the principles for sharing patient-level data. 88

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.