Treatment pathways compared for diabetic peripheral neuropathy

Available treatments for diabetic peripheral neuropathy appear equally effective, with combination therapy an option when monotherapy fails, a recent study found.

Researchers in the United Kingdom performed a multicenter, randomized, double-blind crossover trial in patients with diabetic peripheral neuropathy to compare the effectiveness of guideline-recommended therapies for initial analgesic treatment. Participants were recruited between Nov. 14, 2017, and July 29, 2019, and were included if they had diabetic peripheral neuropathy with a mean score on the daily pain numerical rating scale (NRS) of 4 or higher (range, 0 to 10). Follow-up continued until July 24, 2020.

Patients were randomly assigned to receive one of six ordered sequences from three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin. Monotherapy was given for six weeks and was then supplemented with the combination medication if pain relief was suboptimal, defined as an NRS greater than 3. Treatments were titrated toward the maximum tolerated dose, which was 75 mg/d for amitriptyline, 120 mg/d for duloxetine, and 600 mg/d for pregabalin. Each treatment pathway lasted 16 weeks. The study's primary outcome was the difference in seven-day average daily pain during the final week of each treatment pathway. The results were published Aug. 22 by The Lancet.

Of 140 patients randomly assigned to treatment, 130 were included in the analysis for the primary outcome. For all three pathways, the seven-day average NRS scores at week 16 decreased from a mean of 6.6 at baseline to 3.3 at week 16. The mean difference was −0.1 (98.3% CI, −0.5 to 0.3) for the duloxetine/pregabalin versus the amitriptyline/pregabalin pathway, −0.1 (98.3% CI, −0.5 to 0.3) for the pregabalin/amitriptyline versus the amitriptyline/pregabalin pathway, and 0.0 (98.3% CI, −0.4 to 0.4) for the pregabalin/amitriptyline versus the duloxetine/pregabalin pathway. Mean reduction in NRS score was greater in patients who received combination therapy than those who remained on monotherapy (1.0 vs. 0.2). All treatment pathways yielded similar improvement in quality-of-life measures on the 36-item Short-Form General Health Survey, the Hospital Anxiety and Depression Scale, and the Insomnia Severity Index. Adverse events were dizziness in the pregabalin/amitriptyline pathway, nausea in the duloxetine/pregabalin pathway, and dry mouth in the amitriptyline/pregabalin pathway.

Limitations of the trial included the lack of a placebo group and the high attrition rate, the authors noted. They concluded that all three treatment pathways offered similar analgesic relief for patients with diabetic peripheral neuropathy and that combination therapy was well tolerated and effective when necessary. “Despite large variations in the cost and availability of amitriptyline, duloxetine, and pregabalin across the world, it is reassuring that all three are similarly efficacious in relieving pain,” the authors wrote. “This will have real power to inform future clinical guidelines for the management of [diabetic peripheral neuropathy pain] as available guidelines provide conflicting recommendations.”

An accompanying comment said the study provided good evidence to support the practice of adding medications when adequate pain control is not provided by monotherapy and also showed that available treatments improved nonpain outcomes, such as depression, anxiety, and sleep. The authors called for further research to answer a number of outstanding questions, including the efficacy of nonpharmacological interventions, topical medications versus oral medications, and the role of opioids. “The trial represents one major step forward but many more steps are still needed,” they wrote.