Korean J Pain.  2022 Jan;35(1):59-65. 10.3344/kjp.2022.35.1.59.

Pharmacological interactions between intrathecal pregabalin plus tianeptine or clopidogrel in a rat model of neuropathic pain

• Lee HG
• Kim YO
• Choi JI
• Han XH
• Shin YU
• Yoon MH

• KMID: 2524647
• DOI: http://doi.org/10.3344/kjp.2022.35.1.59

Abstract

Background
There is still unmet need in treating neuropathic pain and increasing awareness regarding the use of drug combinations to increase the effectiveness of treatment and reduce adverse effects in patients with neuropathic pain.
Methods
This study was performed to determine the individual and combined effects of pregabalin, tianeptine, and clopidogrel in a rat model of neuropathic pain. The model was created by ligation of the L5-L6 spinal nerve in male Sprague–Dawley rats; mechanical allodynia was confirmed using von Frey filaments. Drugs were administered to the intrathecal space and mechanical allodynia was assessed; drug interactions were estimated by isobolographic or fixed-dose analyses.
Results
Intrathecal pregabalin and tianeptine increased the mechanical withdrawal threshold in a dose-dependent manner, but intrathecal clopidogrel had little effect on the mechanical withdrawal threshold. An additive effect was noted between pregabalin and tianeptine, but not between pregabalin and clopidogrel.
Conclusions
These findings suggest that intrathecal coadministration of pregabalin and tianeptine effectively attenuated mechanical allodynia in the rat model of neuropathic pain. Thus, pregabalin plus tianeptine may be a valid option to enhance the efficacy of neuropathic pain treatment.

Keyword

Chronic Pain; Clopidogrel; Drug Interactions; Hyperalgesia; Neuralgia; Pregabalin; Rats; Spinal Nerves; Tianeptine

Figure

• 

  Fig. 1 Time course curves of intrathecal pregabalin (A), tianeptine (B) and clopidogrel (C) on the hind paw withdrawal response after spinal nerve ligation. Data are presented as the withdrawal threshold (g). Each line represents the means ± standard error of the mean of 6 rats.

• 

  Fig. 2 Dose response effect of intrathecal pregabalin, tianeptine and clopidogrel (A), or mixture of pregabalin and tianeptine (B) on the hind paw withdrawal response after spinal nerve ligation. Data are presented as the percent of maximal possible effect (% MPE). Each line represents the means ± standard error of the mean of 6 rats. P: pregabalin ED50, T: tianeptine ED50, ED50: 50% effective dose. *P < 0.05, ***P < 0.001, compared with vehicle.

• 

  Fig. 3 Isobologram for the interaction between intrathecal pregabalin and tianeptine. The ED50 values for each agent are plotted on the x axis and y axis, respectively. The experimental ED50 point (E) was significantly different from the theoretical ED50 point (T), indicating an additive interaction in pregabalin and tianeptine. ED50: 50% effective dose.

• 

  Fig. 4 A fixed dose analysis for the interaction between intrathecal clopidogrel (300 μg) and pregabalin. Data are presented as the percent of maximal possible effect (% MPE). Each line represents the means ± standard error of the mean of 6 rats.

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