Relative Efficacy of Pharmacotherapy for Diabetic Peripheral Neuropathy

This systematic review and Bayesian meta-analysis evaluated the relative efficacy of 18 oral pharmacotherapeutic interventions for diabetic peripheral neuropathy.

A systematic review and Bayesian network meta-analysis found that carbamazepine, venlafaxine, and nortriptyline better reduced diabetic neuropathic pain and associated with fewer treatment withdrawals compared with other treatment strategies or placebo. These findings were published in Pain Physician.

Investigators searched publication databases through January 2020 for randomized controlled trials of pharmaceutical interventions for painful diabetic neuropathy. A total of 43 studies met the inclusion criteria for the final analysis.

The included trials were of parallel (88%) or cross-over (12%) designs. Most trials (n=41) were double-blind. The studies were placebo controlled (n=36), active comparators comparisons (n=6), or both (n=1).

Patients (N=7877) were 56% men aged mean 59 (range, 53-66) years with a mean neuropathic pain duration of 3.8 (range, 1.08-7.10) years. Baseline pain on an 11-point numeric rating scale (NRS) was 6.46 (range, 4.95-8.20).

Among the trials, the efficacy outcomes of 30% and 50% pain reduction were reported by 18 and 29 studies, respectively, and the safety outcome of withdrawal due to adverse drug reactions by 39 studies.

A total of 15 intervention comparisons reported 50% pain reduction outcomes, among which 8 comparisons differed significantly. Mirogabalin (odds ratio [OR], 3.25), duloxetine (OR, 2.50), and pregabalin (OR, 2.33) were favored over placebo. In the direct comparisons, mirogabalin (OR, 4.39) and duloxetine (OR, 3.37) were favored over carbamazepine, pregabalin was favored over nortriptyline (OR, 4.10), and mirogabalin (OR, 4.05) and pregabalin (OR, 2.90) were favored over lamotrigine.

For the 30% pain reduction outcome, duloxetine was favored over placebo (OR, 1.97).

Nortriptyline (OR, 0.03), pregabalin (OR, 0.61), and venlafaxine (OR, 0.08) were not favored over duloxetine; mirogabalin was favored over duloxetine and gabapentin (OR, 1.15) but neither nortriptyline (OR, 0.03) nor venlafaxine (OR, 0.09) were favored; nortriptyline (OR, 0.04) and venlafaxine (OR, 0.09) were not favored over lacosamide; nortriptyline (OR, 0.07) and venlafaxine (OR, 0.18) were not favored over lamotrigine; nortriptyline (OR, 0.03) and venlafaxine (OR, 0.08) were not favored over mirogabalin; venlafaxine was not favored over oxcarbazepine (OR, 0.08); and venlafaxine was not favored over pregabalin (OR, 0.13) or tapentadol (OR, 0.10).

Withdrawals due to adverse effects occurred more with desvenlafaxine (OR, 7.86), oxcarbazepine (OR, 6.71), lacosamide (OR, 4.82), venlafaxine (OR, 3.92), amitriptyline (OR, 3.40), duloxetine (OR, 3.39), gabapentin (OR, 3.02), and pregabalin (OR, 2.03) compared with placebo.

In direct comparisons, pregabalin (OR, 0.30) and sodium valproate (OR, 0.09) associated with fewer drug-related withdrawals than oxcarbazepine.

In a cluster analysis, better safety and efficacy profiles were observed for carbamazepine, venlafaxine, and nortriptyline.

The major limitation of this analysis was the heterogeneity in study methods and reporting.

In conclusion, this study found a relative advantage with nortriptyline compared with other drugs, resulting in a 30-50% reduction in pain from the baseline.


Asrar MM, Kumari S, Sekhar BC, Bhansali A, Bansal D. Relative efficacy and safety of pharmacotherapeutic interventions for diabetic peripheral neuropathy: A systematic review and Bayesian network meta-analysis. Pain Physician. 2021;24(1):E1-E14