Is combination therapy a worthwhile OPTION for painful diabetic neuropathy?

Amir has diabetic peripheral neuropathic pain (DPNP). It’s affecting his sleep and making him depressed. He describes burning, electric shock type pains in his feet and a deep, unremitting pain in his lower legs. You have excluded peripheral arterial disease and are confident that clinically it fits with neuropathic pain. Amir’s HbA1c, lipids and BP are not great, but Amir is not interested in these numbers; the thing that really matters to him is his pain which he rates as 8/10 most days. We know that there is no ‘cure’ for neuropathic pain, but if we could reduce Amir’s pain by 50% that would significantly improve his quality of life.

DPNP is a common, disabling and difficult to treat condition. According to the Lancet 2022 it affects about 50% of people with diabetes and of these about half present to us with neuropathic pain. The pain is often moderate to severe, resulting in insomnia, poor quality of life and depression. 

So, how can we help Amir? In line with NICE guidance on neuropathic pain, updated in 2020, you have tried duloxetine, amitriptyline and pregabalin but all 3 have had minimal impact. Is it worthwhile trying a combination of these drugs? Until now I have avoided this. We always want to avoid polypharmacy, we are wary of side-effects and the current NICE guidance does not recommend combinations. However, that guidance may change following the publication the OPTION-DM trial in this week’s Lancet. Funded by the National Institute of Health Research (i.e. not pharma) and the largest such study to date, its findings are very relevant to us and Amir. 

The study included patients (n=140) across the UK with DPNP who had daily pain that they rated as at least 4/10 in severity. The trial looked at initial monotherapy and then compared three combination treatment pathways over 16 weeks in non-responders i.e. patients like Amir. I really like the design of this trial as it mirrors clinical practice, and it helps to answer a common clinical conundrum – what to do next in the patient who has not responded to monotherapy?

The combinations compared were amitriptyline supplemented with pregabalin, pregabalin with amitriptyline and duloxetine with pregabalin. Each pathway had initial monotherapy for 6 weeks. At 6 weeks, if pain scores were mild (< 3/10) they were classed as responders and continued on monotherapy. A significant finding is that only a third responded well to monotherapy, which fits with clinical experience. If at 6 weeks pain remained ≥ 4/10, they were randomised to one of the 3 combination pathways.  Amitriptyline was titrated to maximum of 75mg a day, duloxetine to 120mg and pregabalin to 600mg. The trial was blinded, but there was no placebo combination. This is a shame, as you would expect that with a pain study the placebo effect may be significant, however it was not felt to be ethically justifiable. 

Results? At the end of the study, the average pain scores over a week were reduced by 50% from a mean of 6.6 to 3.3 in all 3 treatment pathways with no significant difference between them. A 50% reduction in pain scores is a successful outcome for neuropathic pain.  The combination therapies were also surprisingly well tolerated, although I expect that ‘real-life’ tolerability will not be so good! The authors conclude ‘our study can give confidence that any of these drugs or combinations, if titrated carefully to maximum tolerated doses, can result in similar levels of pain relief’ and argue that this study should impact future guidelines.

So, what are the implications for Amir? As monotherapy has not worked, one of these three combinations is worth a trial over the next 16 weeks titrating up to the maximal tolerated dose. We should still encourage him to be interested in his HbA1c and BP as we know that chronic hyperglycaemia and cardiovascular risk factors increase the risk and severity of DPNP.  If his pain is better, his mood will lift and then he may be more willing to engage with his diabetes and CV risk factor control giving a double win.