This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.
Diabetes can cause nerve damage (diabetic neuropathy), which leads to pain in the feet, legs and hands. Research found combinations of standard medicines (pregabalin, amitriptyline, and duloxetine) provided relief from pain in people for whom one drug alone was not sufficient.
1 in 4 people with diabetes experience painful diabetic neuropathy. Before this study, there was little evidence to guide which medication people with the condition should start on. There was also a lack of evidence on whether combining 2 pain-relieving medications is safe and effective (if pain is unmanageable with one). Many doctors prescribe 2 medications in this situation.
This study (a randomised controlled trial) compared the effectiveness of pregabalin, amitriptyline, and duloxetine. It showed that combinations of these drugs were safe, and equally effective at relieving pain.
Clinicians can be reassured that patients can be started on any one of the 3 medications and have another added, if needed. They could discuss the side effects associated with each medication and ask the patient which they would prefer.
For more information on peripheral neuropathy, visit the NHS website.
The issue: can drugs for diabetic neuropathy be used in combination?
According to Diabetes UK, more than 5 and half million people will have diabetes by 2030. Diabetes can cause nerve damage that can lead to severe pain in the feet, legs, and hands (diabetic peripheral neuropathy). It can feel like burning, electric shocks, or a deep ache. 1 in 4 people with diabetes have painful diabetic neuropathy and for most, the pain is persistent. It often leads to poor sleep and quality of life, as well as mood disorders (such as depression).
Guidelines from the National Institute for Health and Care Excellence (NICE) recommend medications, including amitriptyline, duloxetine, and pregabalin, for pain relief. But these treatments taken alone provide only partial benefit; pain severity drops by about half in around half of people. The drugs may have side effects such as dry mouth, dizziness, and nausea.
Many clinicians prescribe 2 medications for people whose pain is not adequately controlled by 1. However, there is little evidence to support using these drugs in combination. Researchers investigated the effectiveness and safety of drug combinations for painful diabetic neuropathy.
What’s new?
The study included 130 people with painful diabetic neuropathy. They were being treated at 13 primary and secondary care centres in the UK.
People were randomly allocated to one of 3 treatment pathways:
- amitriptyline with pregabalin, if needed
- duloxetine with pregabalin, if needed
- pregabalin with amitriptyline, if needed.
People took the first drug for 6 weeks; the second was added for a further 10 weeks if the pain was not controlled. They then moved on to another pathway. For each pathway, the dose of the drug was gradually increased to the level a person could tolerate (without the side effects becoming too much).
The study design intended for people to complete the pathways one after the other (in a randomised order) for approximately 50 weeks overall. Some people dropped out of the trial itself, but 84 completed at least 2 pathways.
The researchers found that, during the final week of each pathway:
- all 3 treatment pathways reduced pain to a similar degree
- 2 treatments in combination provided additional pain relief in some people whose pain did not respond to one medication alone.
Sleep and quality of life were improved to a similar degree for all 3 pathways; and the costs for each of the pathways were roughly the same.
Side effects were as expected for each drug. For instance, several people experienced dizziness with pregabalin, nausea with duloxetine, and dry mouth with amitriptyline. The 3 pathways had similar numbers of serious side effects. Combination treatment was generally well tolerated, and few people discontinued treatment. People were most likely to continue with pregabalin supplemented by amitriptyline.
Why is this important?
The study should reassure clinicians that any of these drugs, or drug combinations, can provide effective pain relief. Combination treatment was safe, and helped people whose pain was not adequately managed with one medication. All trialled combinations of pregabalin, amitriptyline, and duloxetine provided similar pain relief.
One of the study’s strengths is that it reflects clinical practice, the researchers say. Most patients start taking one medication and need to begin taking another after a few months if their pain is still not managed.
The study took longer to carry out than other clinical trials, which may partly explain why 1 in 3 people did not complete the planned 50 weeks.
What’s next?
Clinicians could discuss the benefits and drawbacks of each medication with patients, to explore their preferences. The best treatment pathway for an individual may depend on the side effects people experience.
The study was not set up to compare single versus combination therapy. However, the findings suggest that people whose pain is not managed adequately with one medication could be treated with 2, the researchers say.
This study included people with painful diabetic neuropathy. But many others experience painful neuropathy from other causes (such as cancer or multiple sclerosis). Overall, almost 1 in 10 people in the UK have painful neuropathy. Treatments (including the medications from this study) and guidelines for painful neuropathy are similar, regardless of the cause. Therefore, the findings from this study may be applicable to neuropathic pain caused by other conditions. The researchers say NICE could consider updating its guidelines on the management of neuropathic pain from all causes.
You may be interested to read
This Alert is based on: Tesfaye S, and others. 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: 680–690.
A report including the cost-effectiveness analysis and a plain language summary: Tesfaye S, and others. Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT. Health and Technology Assessment 2022; 16: 1–138.
Funding: This study was funded by NIHR Health and Technology Assessment Programme.
Conflicts of Interest: Several authors have received fees and funding from pharmaceutical companies. See the original paper for conflicts of interest.
Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) at the time of publication. They do not necessarily reflect the views of the NHS, the NIHR or the Department of Health and Social Care.
