OPTION-DM trial
Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus trial (OPTION-DM)
Study outputs
The problem
Peripheral neuropathy is a common condition among people with diabetes, and around one in four people with diabetes have experienced neuropathic pain in their feet, legs or hands. The pain is often both chronic and severe, impacting negatively on people’s ability to walk, sleep and perform everyday tasks.
The National Institute for Health and Care Excellence (NICE) recommends a choice of four drugs; amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for painful diabetic neuropathy. There is little evidence on which is best, nor on whether introducing a second drug in combination results in additional benefit - most current guidelines do not recommend this due to insufficient evidence.
Furthermore, few studies have investigated the effect of interventions on quality of life, patient functioning, mood, or sleep; and scarce data are available on which patients respond to a specific drug.
In 2016 the National Institute for Health Research commissioned Sheffield Teaching Hospitals alongside the University of Sheffield to undertake a clinical trial to answer this question.
Our aim
To identify the most effective treatment combinations for patients with painful diabetic neuropathy.
What we did and what we found
The participants in the Option-DM trial tried three treatment pathways, each comprising 16 weeks of treatment (see below). Participants started their first treatment pathway by receiving a drug for six weeks, starting at a low dose and increasing gradually to the right dose for the participant.
At six weeks, participants were asked about their pain, mood, sleep, overall quality of life and any reactions to the drug. If this didn’t reduce their pain enough they could start a second drug in addition to (or in place of) the first, again starting at a low dose and increasing to the best-tolerated level.
At the end of the 16 weeks of treatment participants again reported their pain, mood, sleep, quality of life and adverse reactions.
The three pathways were given in random order:
- Amitriptyline, with pregabalin added if needed
- Duloxetine, with pregabalin added if needed
- Pregabalin, with amitriptyline added if needed
What we found
The trial completed recruitment in 2020, with 140 participants being randomised. The three treatments showed similar levels of pain control and were generally comparable in other aspects. Participants rated their pain at an average of 6.6 points on a 0-10 scale prior to starting the first treatment, and this was reduced to 3.3/10 at the end of all three pathways.
We also found that the two-drug combinations provided added pain relief among people that had not responded well enough when using just one. The number of people using the two-drug combination was similar across the three pathways.
So if pain reduction was about the same in all treatments, which should people take? We did find some differences across the treatment options.
We found that people given amitriptyline first reported better sleep than those given duloxetine first, but overall this was the least preferred pathway among the participants that rated all three (pregabalin followed by amitriptyline being the most). Amitriptyline was also associated with worse pain control among people with low moods when compared to other pathways.
There were significantly fewer discontinuations due to side effects when taking pregabalin. However, side effects were common on all pathways, with an excess of self-reported dizziness when taking pregabalin (with or without amitriptyline); nausea when taking duloxetine (with or without pregabalin); and dry mouth when taking amitriptyline (with or without pregabalin).
Some differences were seen in responses to the quality of life questionnaires, but these differences were generally small and were not consistently in favour of one pathway.
Implications of our results and future work
The decision of the best therapeutic approach is likely to be person-specific and should take into account what side effects they are willing or able to tolerate. Overall pain control was similar among the three options and exceeded the pain relief found in previous trials where participants received an inactive placebo treatment.
Typically in practice, patients are initially prescribed a first-line drug. If this is not sufficiently effective, they will be switched to a different drug. Our results suggest the introduction of a second drug in combination can provide additional pain relief and is well tolerated.
Our study can influence future treatment guidelines for DPNP, but also chronic neuropathic pain treatment in general (estimated to affect 8-9% of the UK population) because current guidelines are largely generic. This will benefit patients, as well as general practitioners, diabetes specialists, pain specialists, neurologists, general physicians and other medical and allied healthcare professionals managing DPNP, by the provision of improved treatment pathways.
Some first-line drugs might not be available in resource-limited countries, but our study gives confidence that any of these drugs or drug combinations, if titrated carefully to maximum tolerated doses, can provide similar pain relief.
What will we do with the results?
A summary of results was sent to study participants via participating sites. The results were published in The Lancet and disseminated to patient groups and healthcare professionals, through a press release, via social media and through Diabetes UK. We will also share our findings with key policymakers, including NICE and s well as international bodies such as the American Diabetes Association.
Future work
There is currently some reluctance amongst clinicians to prescribe these medications to older people with painful diabetic neuropathy. We will therefore undertake some additional analyses, exploring whether there were any differences in our study outcomes or side effects in older versus younger participants.
How did we involve patients?
People with diabetes have worked with us throughout the study, in development of the initial study design, as well as overseeing the delivery of the study, ensuring that the patient perspective was considered throughout, including in decision making regarding protocol amendments and participant recruitment strategies. They also helped in developing the study materials - ensuring these were accessible for potential participants - and inputted into the summary of the results.
Project team
| Name | Role | Organisation | Contact |
|---|---|---|---|
| Professor Solomon Tesfaye | Chief Investigator | Sheffield Teaching Hospitals | solomon.tesfaye@sth.nhs.uk |
| Dr Dinesh Selvarajah | Co-Investigator | Sheffield Teaching Hospitals/University of Sheffield | d.selvarajah@sheffield.ac.uk |
| Professor Cindy Cooper | Director, CTRU | CTRU, University of Sheffield |
+44 114 222 0743 |
| David White | Research Associate | CTRU, University of Sheffield |
+ 44 114 222 0807 |
| Jennifer Petrie | Trial Manager | CTRU, University of Sheffield |
+44 114 222 0676 |
| Katie Sutherland | Research Assistant | CTRU, University of Sheffield |
+44 114 222 4023 |
| Zoe Furniss | Trial Support Officer | CTRU, University of Sheffield |
+44 114 215 9122 |
| Steven Julious | Statistician | Medical Statistics Group, University of Sheffield |
+44 114 222 0709 |
| Mike Bradburn | Statistician | CTRU, University of Sheffield |
+44 114 222 0706 |
| Data Management Team | CTRU, University of Sheffield |
Participating sites
England
| Site | Investigator |
|---|---|
| Sheffield Teaching Hospitals NHS Foundation Trust | Professor Solomon Tesfaye |
| Ipswich Hospital NHS Trust | Dr Gerry Rayman |
| Tameside Hospital NHS Foundation Trust | Dr Edward Jude |
| Lancashire Teaching Hospitals NHS Foundation Trust | Professor Satyan Rajbhandari |
| Aintree University Hospital | Dr Uazman Alam |
| Nottingham University Hospitals NHS Trust | Dr Ravikanth Gouni |
| Harrogate and District NHS Foundation Trust | Dr Deirdre Maguire |
| Countress of Chester Hospital NHS Foundation Trust | Dr Haris Ahmed |
| Gateshead Health NHS Foundation Trust | Dr Vasileios Tsatlidis |
| King's College Hospital NHS Foundation Trust | Dr Prashanth Vas |
| Royal Wolverhampton NHS Trust | Dr Christian Hariman |
Scotland
| Participating site | Main contact |
|---|---|
| University Hospital Monklands - NHS Lanarkshire | Dr Marion Devers |
| University Hospital Hairmyres - NHS Lanarkshire | Dr Claire McDougall |
Sponsor
This project is funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 15/35/03). Any views or opinions expressed are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.