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Am Fam Physician. 2023;107(3):316-317

Clinical Question

Are amitriptyline, duloxetine (Cymbalta), and pregabalin (Lyrica) effective in decreasing pain in adults with diabetic peripheral neuropathy?

Bottom Line

Adults with painful diabetic peripheral neuropathy had similar degrees of improvement with monotherapy using amitriptyline, duloxetine, and pregabalin. There was even greater improvement with subsequent combination therapy regardless of initial choice of medication. (Level of Evidence = 1b)


The researchers enrolled 130 adults with diabetes mellitus and pain associated with distal symmetric polyneuropathy for at least three months. In this crossover trial, the participants were randomly assigned to three 16-week pathways separated by a two-week washout period: oral amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin. Each pathway started with a two-week period in which doses were titrated to the maximum tolerated dose. This was followed by six weeks of maintenance monotherapy. At the end of six weeks, those with a pain level of 3 or less out of 10 were classified as responders and remained on monotherapy for 10 weeks. Nonresponders received the second drug for 10 weeks. During the subsequent 10 weeks, the researchers titrated medication doses to maintain pain levels at 3 or less out of 10. At the end of 16 weeks, the researchers stopped all study drugs for a two-week washout period, and the participants started the next drug combination.

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POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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