Antinociceptive Synergism of Gabapentin and Nortriptyline in Mice with Partial Sciatic Nerve Ligation

Abstract

Background and Methods: Neuropathic pain results from nerve injury, and gabapentin, an antiepileptic drug, has been approved for the treatment of several types of neuropathic pain. On the other hand, nortriptyline, an antidepressant drug, has been suggested as an alternative treatment. In partial sciatic nerve ligation (PSNL) mice, the interaction of gabapentin with nortriptyline was evaluated by the hot plate assay using isobolographic analysis. Results: Gabapentin (3-100 mg/kg, i.p.) or nortriptyline (1-30 mg/kg, i.p.) induced dose-dependent antinociception, with an ED₅₀ of 11.60 ± 0.54 mg/kg for gabapentin and of 5.16 ± 0.21 mg/kg for nortriptyline. The potency of gabapentin and nortriptyline in PSNL mice at 7 and 14 days after ligation was significantly increased (p < 0.05). Coadministration of gabapentin with nortriptyline, at a 1:1 ratio of their ED₅₀, had a synergistic effect, with an interaction index of 0.311 and 0.348 for these mice at 7 and 14 days, respectively. Conclusion: The data showed a synergy in antinociception at a gabapentin-to-nortriptyline ratio of 1:1 in PSNL mice. This finding suggests that this combination could provide a therapeutic alternative that can be used for neuropathic pain management.

The efficacy of combination treatment of gabapentin and electro-acupuncture on paclitaxel-induced neuropathic pain

“…Six to eight mice were used in each GBT group (3, 30, and 100 mg/kg, i.p.) [ 42 43 ]. In the control group, four mice received the same volume of PBS, intraperitoneally.…”

α2- and β2-Adrenoreceptor-Mediated Efficacy of the Atypical Antidepressant Agomelatine Combined With Gabapentin to Suppress Allodynia in Neuropathic Rats With Ligated Infraorbital or Sciatic Nerve

“…As it rapidly appeared that, under acute treatment conditions, agomelatine was ineffective on its own, we investigated whether it could develop anti-allodynic effects when combined with an anticonvulsant, namely gabapentin. Indeed, an abundant literature has shown that combined treatments with an antidepressant and an anticonvulsant most often produce synergistic effects, with much better alleviation of neuropathic pain than that expected from the sum of the effects expected from each drug alone ( Tomic et al, 2010 ; Miyazaki and Yamamoto, 2012 ; Gilron et al, 2013 ; Miranda et al, 2015 ). In both CCI-SN and CCI-ION rats, we found here that although gabapentin was administered at a dose, 50 mg/kg i.p., which produces no sedative effect and only minor, or even no, anti-allodynic effect ( Christensen et al, 2001 ; Patel et al, 2001 ; De Vry et al, 2004 ; Vanelderen et al, 2013 ), co-treatment with agomelatine + gabapentin effectively produced marked anti-allodynic effects.…”

Synergistic Interaction of a Gabapentin‐ Mangiferin Combination in Formalin‐Induced Secondary Mechanical Allodynia and Hyperalgesia in Rats Is Mediated by Activation of NO‐Cyclic GMP‐ATP‐Sensitive K+ Channel Pathway

“…Gabapentin injected intradermally into the hindpaw can induce analgesia [Todorovic et al, ] and gabapentin is also effective in acute and chronic models of inflammatory pain [Singh et al, ; Heughan and Sawynok et al, ; Hurley et al, ] and reverses allodynia and hyperalgesia induced by 1% formalin [Salinas‐Abarca et al, ]. Gabapentin can decrease allodynia induced by nerve lesions in a neuropathic rat model [Chen et al, ; Field et al, ; Mixcoatl‐Zecuatl et al, ; Yamama et al, ; Miranda et al, ; Corona‐Ramos et al, ; Espinosa‐Juárez et al, ]. The antiallodynic effect of gabapentin may result from binding to the α2δ1 subunit of L‐type voltage‐dependent Ca 2+ channels [Gee et al, ] although it could activate other targets.…”

“…However, gabapentin has been co‐administered with (1) NSAIDs like naproxen [Hurley et al, ], meloxicam [Espinosa‐Juárez et al, ], ibuprofen [Yoon and Yaksh, ], diclofenac [Picazo et al, ] and metamizol [Ortega‐Varela et al, ]. (2) antidepressants like venlafaxine [Rode et al, ], nortriptyline [Miranda et al, ], and amitriptyline [Heughan and Sawynok, ]. (3) The opioids morphine [Shimoyama et al, ; De la O‐Arciniaga et al, 2009) and tramadol [Granados‐Soto and Argüelles, ].…”