Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain

Abstract

Background: Neuropathic pain is a chronic pain due to disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Analgesic drugs combined can reduce pain intensity and side effects. Here, we studied the analgesic effect of nimesulide, nefopam, and morphine with different mechanisms of action alone and in combination with other drugs in chronic constriction injury (CCI) model of neuropathic pain.

Methods: Male Wistar rats (n = 8) weighing 150-200 g were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. Nimesulide (1.25, 2.5, and 5 mg/kg), nefopam (10, 20, and 30 mg/kg), and morphine (1, 3, and 5 mg/kg) were injected 30 minutes before surgery and continued daily to day 14 post-ligation. In the combination strategy, a nonanalgesic dose of drugs was used in combination such as nefopam + morphine, nefopam + nimesulide, and nimesulide + morphine. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were, respectively, used as pain behavioral tests. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post injury.

Results: Nefopam (30 mg/kg) and nimesulide (5 mg/kg) blocked mechanical and thermal allodynia; the analgesic effects of morphine (5 mg/kg) lasted for 7 days. Allodynia was completely inhibited in combination with nonanalgesic doses of nefopam (10 mg/kg), nimesulide (1.25 mg/kg), and morphine (3 mg/kg).

Conclusions: It seems that analgesic drugs used in combination, could effectively reduce pain behavior with reduced adverse effects.

Keywords: combination therapy; morphine; nefopam; neuropathy; nimesulide.

Fig. 1

Paw withdrawal threshold in response to von Frey filaments before and at several time points after surgery in the saline-treated CCI group, saline-treated sham group, and drug-treated CCI group. Nefopam (10, 20, and 30 mg/kg (A)), Nimesulide (1.25, 2.5, and 5 mg/kg (B)), morphine (1, 3, and 5 mg/kg (C)) were injected i.p. Results are expressed as the mean ± SEM of 8 animals per group. Nef: Nefopam, Nim: Nimesulide, Mor: Morphine. Asterisks indicate a significant difference between post surgery days compared with day 0 (^*P < 0.05, ^†P < 0.01, ^‡P < 0.001).

Fig. 2

The frequency of paw withdrawal in response to acetone before and at several time points after surgery in the saline-treated CCI group, saline-treated sham group, and drug-treated CCI group. Nefopam (10, 20, and 30 mg/kg (A)), Nimesulide (1.25, 2.5, and 5 mg/kg (B)), morphine (1, 3, and 5 mg/kg (C)) were injected i.p. Results are expressed as the mean ± SEM of 8 animals per group. Nef: Nefopam, Nim: Nimesulide, Mor: Morphine. Asterisks indicate a significant difference between post surgery days compared with day 0 (^*P < 0.05, ^†P < 0.01, ^‡P < 0.001).

Fig. 3

Paw withdrawal threshold in response to von Frey filaments (A) and the frequency of paw withdrawal in response to acetone (B) before and at several time points after surgery in saline-treated CCI group, saline-treated sham group and drug-treated CCI groups in combination: (morphine 3 mg/kg + nefopam 10 mg/kg, morphine 3 mg/kg + nimesulide 1.25 mg/kg, nimesulide 1.25 mg/kg + nefopam 10 mg/kg) were injected i.p. Results are expressed as the mean ± SEM of 8 animals per group. Nef: Nefopam, Nim: Nimesulide, Mor: Morphine. Asterisks indicate a significant difference between post surgery days compared with day 0 (^*P < 0.01, ^†P < 0.001).