Pharmacological Interaction Between Cannabidiol and Tramadol on Experimental Diabetic Neuropathic Pain: An Isobolographic Analysis

Cannabis Cannabinoid Res. 2024 Jun;9(3):728-739. doi: 10.1089/can.2021.0242. Epub 2023 May 19.


Introduction: Diabetic neuropathies are the most prevalent chronic complications of diabetes, characterized by pain and substantial morbidity. Although many drugs have been approved for the treatment of this type of pain, including gabapentin, tramadol (TMD), and classical opioids, it is common to report short-term results or potentially severe side effects. TMD, recommended as a second-line treatment can lead to unwanted side effects. Cannabidiol (CBD) has been gaining attention recently due to its therapeutic properties, including pain management. This study aimed to characterize the pharmacological interaction between CBD and TMD over the mechanical allodynia associated with experimental diabetes using isobolographic analysis. Materials and Methods: After diabetes induction by streptozotocin (STZ), diabetic rats were systemically treated with CBD or TMD alone or in combination (doses calculated based on linear regression of effective dose 40% [ED40]) and had the mechanical threshold evaluated using the electronic Von Frey apparatus. Both experimental and theoretical additive ED40 values (Zmix and Zadd, respectively) were determined for the combination of CBD plus TMD in this model. Results: Acute treatment with CBD (3 or 10 mg/kg) or TMD (2.5, 5, 10, or 20 mg/kg) alone or in combination (0.38+1.65 or 1.14+4.95 mg/kg) significantly improved the mechanical allodynia in STZ-diabetic rats. Isobolographic analysis revealed that experimental ED40 of the combination (Zmix) was 1.9 mg/kg (95% confidence interval [CI]=1.2-2.9) and did not differ from the theoretical additive ED40 2.0 mg/kg (95% CI=1.5-2.8; Zadd), suggesting an additive antinociceptive effect in this model. Conclusions: Using an isobolographic analysis, these results provide evidence of additive pharmacological interaction between CBD and TMD over the neuropathic pain associated with experimental diabetes induced by STZ.

Keywords: diabetes; isobologram; mechanical allodynia; neuropathic pain; pharmacological interaction; streptozotocin.

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use
  • Animals
  • Cannabidiol* / pharmacology
  • Diabetes Mellitus, Experimental* / complications
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetic Neuropathies* / drug therapy
  • Drug Interactions
  • Drug Therapy, Combination
  • Hyperalgesia / drug therapy
  • Male
  • Neuralgia / drug therapy
  • Rats
  • Rats, Sprague-Dawley
  • Tramadol* / pharmacology
  • Tramadol* / therapeutic use


  • Cannabidiol
  • Tramadol
  • Analgesics, Opioid
  • Analgesics