Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial



The trial aimed to investigate the effectiveness of exogenous melatonin as an adjuvant to pregabalin for relief of pain in patients suffering from painful diabetic neuropathy (PDN).

Patients and methods

This randomized, double-blind, placebo-controlled trial was carried out between October 2019 and December 2020 in an outpatient specialty clinic in Iran. One-hundred-three type 2 diabetic patients suffering from PDN were randomized into either the melatonin group (n = 52) or the placebo group (n = 51). Besides pregabalin at a dose of 150 mg per day, patients started with melatonin or an identical placebo, at a dose of 3 mg/day at bedtime for 1 week, which was augmented to 6 mg/day for further 7 weeks. The primary outcomes were changes in mean NRS (numerical rating scale) pain score from baseline to endpoint and responder rate (patients with a reduction of 50% and higher in average pain score compared with baseline). Secondary endpoints were changes in mean NRS pain-related sleep-interference score, overall improvement evaluated by Patient and Clinical Global Impressions of Change (PGIC, CGIC), and impact of the intervention on patient’s Health-related quality of life (QOL). All analyses were conducted on an Intention-to-Treat (ITT) analysis data set.


At the study endpoint, treatment with melatonin resulted in a considerably higher reduction in the mean NRS pain score in comparison with placebo (4.2 ± 1.83 vs. 2.9 ± 1.56; P-value < 0.001). In terms of treatment responders, a greater proportion of melatonin-treated patients satisfied the responder criterion than placebo-treated patients (63.5% vs. 43.1%). Melatonin also reduced pain-related sleep interference scores more than did placebo (3.38 ± 1.49 vs. 2.25 ± 1.26; P-value < 0.001). Further, at the endpoint, more improvement was also seen in terms of PGIC, CGIC, and Health-related QOL in patients treated with melatonin than placebo. Melatonin was also well tolerated.


The present results showed that melatonin as an adjunct therapy to pregabalin might be helpful for use in patients with PDN. However, confirmation of these results requires further studies.

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Availability of data and material

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request up to 2 years after publication.


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Vice-Chancellor of Research and Technology of Hamadan University of Medical Sciences is acknowledged here for supporting this study (Hamadan, Iran, Grant Number: 9808286522). This grant was just for the provision of medicine and placebo and was not assigned to the manuscript writing, editing, and publication fee. The authors thank all patients for helping and participating in the study.


Vice-Chancellor of Research and Technology of Hamadan University of Medical Sciences provided support for this study (Hamadan, Iran, Grant Number: 9808286522). This grant was just for the provision of medicine and placebo and was not assigned to the manuscript writing, editing, and publication fee.

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Conceptualization: Mehrpooya and Shokri; methodology: Mehrpooya, Shokri, Mohammadi, and Sajedi; data acquisition: Sajedi and Shokri; statistical analysis: Mohammadi; writing—original draft preparation: Shokri; writing—review and editing: Mehrpooya and Mohammadi; interpretation of the results and approval of the final manuscript: all authors.

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Correspondence to Maryam Mehrpooya.

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Shokri, M., Sajedi, F., Mohammadi, Y. et al. Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial. Eur J Clin Pharmacol (2021).

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  • Painful diabetic neuropathy
  • Oxidative stress
  • Inflammation
  • Melatonin
  • Pregabalin