ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Treatment of neuropathic pain in diabetic rats with synergistic combinations of Nortriptyline + Tramadol and Nortriptyline + Ibuprofen
- MG
M Gicela Pérez-Hernández 1
- AS
Alberto Sesena-Rubfiaro 2
- ÁD
Ángel D. Trillo-Arenazas 3
- YC
Yolitzy Cárdenas 3
- MH
Miguel Huerta 3
- XT
Xóchitl Trujillo 3
- EA
Enrique A. Sánchez-Pastor 3
- IM
Irene M Díaz-Reval 3
1. Universidad de Colima Facultad de Enfermeria, Colima, Mexico
2. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland, Kuopio, Finland
3. University Center for Biomedical Research, University of Colima, Colima, Mexico
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Abstract
Introduction: Neuropathic pain in diabetic patients is very difficult to treat and does not respond to conventional analgesic treatments. It has been observed that tricyclic antidepressants are able to reduce this type of pain. In some animal experimental models, drug combinations have yielded better results. Thus, this study analyzed the type of synergism produced by the combinations of Nortriptyline + Tramadol and Nortriptyline + Ibuprofen in streptozotocin-induced diabetic rats. Methodology: Hyperglycemia was induced by administering 65 mg/kg i.p. of streptozotocin to Wistar rats. The formalin model was used to evaluate hyperalgesia with administration of formalin at 0.5%. The effects of tramadol, ibuprofen, and nortriptyline as monotherapies were evaluated. The doses administered in combination were determined using the mean effective doses of each drug and the constant-ratio method. An isobolographic analysis was performed to determine the type of synergism. Results: Nortriptyline, Tramadol, and Ibuprofen showed an antihyperalgesic effect dose-dependent. Nortriptyline was the most effective and most potent; its maximum effect was 96.67 ± 1.52%, and the ED50 was 3.0 mg/kg. The Nortriptyline + Tramadol combination showed similar efficacy to that of Nortriptyline monotherapy. However, the ED50 for its combination was significantly lower (0.97 mg/kg). The isobolographic analysis showed that this combination generates supra-additive synergism, which was confirmed with the interaction index (γ=0.237). The combination of Nortriptyline + Ibuprofeno exhibited a maxim effect of 81.36 ± 2.36%, and the ED50 was 15.6 mg/kg, its interaction index was less than the unit (γ=0.699) this indicates a supra-additive synergism. Conclusion: Our study demonstrates that combinations of Nortriptyline with either Tramadol or Ibuprofen are more effective at lower doses than the drugs alone. A supra-additive synergism has been observed for both combinations, which may be useful in the management of neuropathic pain caused by diabetes.
Summary
Keywords
diabetes, Ibuprofen, neuropathic pain, Nortriptyline, Synergism, Tramadol
Received
19 February 2026
Accepted
13 August 2026
Copyright
© 2026 Pérez-Hernández, Sesena-Rubfiaro, Trillo-Arenazas, Cárdenas, Huerta, Trujillo, Sánchez-Pastor and Díaz-Reval. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Irene M Díaz-Reval
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