Beyond pain relief: comparing two combination therapies for diabetic peripheral neuropathy

Aims: Diabetic peripheral neuropathic pain (DPNP) is a multifactorial chronic condition with significant impact on pain perception, sleep quality, and affective status. Although several first-line agents are available, monotherapy frequently provides incomplete relief or is limited by tolerability. Combination therapy targeting complementary mechanisms is therefore increasingly used in clinical practice. This study aimed to compare the effectiveness and safety of two commonly prescribed combination regimens, pregabalin plus nortriptyline (PG-NT) and pregabalin plus duloxetine (PG-DLX), in a real-world cohort of patients with DPNP, with particular emphasis on multidimensional outcomes beyond pain intensity alone.

Methods: A retrospective prospective cohort study was conducted at a tertiary care center in South India. Sixty adults with type 2 diabetes and clinically diagnosed DPNP, treated with either PG-NT or PG-DLX for at least two months, were included and followed prospectively for nine weeks. Pregabalin was administered at 150–300 mg/day in both groups; nortriptyline was titrated between 10 and 75 mg/day, while duloxetine was given at a fixed dose of 60 mg/day. Efficacy was assessed using validated instruments capturing multiple symptom domains: pain intensity (Visual Analogue Scale, VAS), sleep disturbance (Insomnia Severity Index, ISI), and mood symptoms (Hospital Anxiety and Depression Scale, HADS).

Results: After nine weeks, VAS scores decreased to 2.76 ± 0.91 in the PG-NT group and 2.57 ± 1.30 in the PG-DLX group. The mean change was −1.35 (95% CI −1.65 to −1.04; p<0.001) for PG-NT and −2.23 (95% CI −2.69 to −1.84; p<0.001) for PG-DLX, with a moderate between-group effect size favoring PG-DLX. Improvements in sleep quality were observed in both groups but were greater in the PG-DLX group, as reflected by larger reductions in ISI scores. Anxiety symptoms improved significantly with both regimens: −1.41 (95% CI −1.91 to −0.90; p<0.001) with PG-NT and −2.00 (95% CI −2.70 to −1.29; p<0.001) with PG-DLX. Depressive symptoms (HADS-D) improved significantly only in the PG-DLX group (−1.70; 95% CI −2.50 to −0.90; p<0.001). Differences between regimens suggest a potential advantage of pregabalin–duloxetine for selected multidimensional outcomes.

Conclusions: Differences between regimens suggest a potential advantage of pregabalin duloxetine combination for selected multidimensional outcomes.

Comments: This study provides real-world evidence supporting combination therapy for DPNP and highlights clinically relevant differences between pregabalin-based regimens. While both combinations achieved statistically significant pain reduction, PG-DLX demonstrated consistently greater improvements across pain, sleep, and mood domains, suggesting a broader therapeutic impact. These multidimensional benefits are particularly relevant in chronic neuropathic pain, where non-pain symptoms substantially contribute to disability and reduced quality of life.

The findings are broadly consistent with evidence from randomized trials such as OPTION-DM, which support pregabalin-based combination strategies, while extending current knowledge by emphasizing differential effects on secondary outcomes. Limitations include the non-randomized design, small sample size, and short follow-up, underscoring the need for larger, longer-term comparative studies to guide individualized treatment selection in DPNP.

Fabiana Picconi

Reference. Dasari PC, Chandu A, Bodala M, Bandaru SP, Chundu UC, Nelluri PS, Thiriveedhi S, Bhatti C, Maharjan S. Comparative cohort study of pregabalin nortriptyline and pregabalin duloxetine in the management of diabetic peripheral neuropathic pain. Sci Rep. 2025 Dec 17;15(1):43980. doi: 10.1038/s41598-025-27617-2. PMID: 41407775; PMCID: PMC12711948.

🔗 https://www.nature.com/articles/s41598-025-27617-2