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. 2019 Jun 27;10:711.
doi: 10.3389/fphar.2019.00711. eCollection 2019.

Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain: A Preclinical Study

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Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain: A Preclinical Study

Yannick Fotio et al. Front Pharmacol. .
Free PMC article

Abstract

Neuropathic pain (NP) is a common public health problem that poses a major challenge to basic scientists and health-care providers. NP is a complex problem with an unclear etiology and an often-inadequate response to current medications. Despite the high number of drugs available, their limited pharmacological efficacy and side effects hamper their chronic use. Thus, the search for novel treatments is a priority. In addition to pharmaceuticals, natural extracts and food supplements are often used to help treating patients with NP. One such supplement is Noxiall®, a commercially available combination of N-Palmitoylethanolamide (PEA), beta-caryophyllene; carnosic acid and myrrh. Here, we compare the efficacy of Noxiall® to that of the medications gabapentin and pregabalin in the NP model of chronic constriction injury (CCI) using sciatic nerve ligation in mouse. Following CCI, mice developed a significant increase in mechanical allodynia and thermal hyperalgesia. Results showed that administration of either Noxiall®, pregabalin, or gabapentin significantly attenuated mechanical allodynia. The magnitude of the Noxiall® effect was comparable to that of gabapentin or pregabalin. In addition, co-administration of non-effective doses of pregabalin and Noxiall® resulted in a significant decrease in NP, suggesting an additive efficacy. Noxiall® was efficacious also in reducing CCI-induced thermal hyperalgesia. These findings support the rationale of using natural remedies in conjunction with classical pharmacological agents to treat chronic NP.

Keywords: PEA; beta-caryophyllene; carnosic acid; gabapentin; myrrh; neuropathic pain; nutraceutical.

Figures

Figure 1
Figure 1
Effect of oral treatment with Noxiall® (Nox) and gabapentin (GBP) on chronic constriction injury (CCI)-induced mechanical allodynia in mice. Animals were treated twice a day with Noxiall® (PEA 300 mg/10 ml/kg, Myrrh 25 mg/10 ml/kg, beta-caryophyllene (BCP) 5 mg/10 ml/kg and Rosmarinus officinalis 6.16 mg/10 ml/kg), gabapentin (100 mg/10 mg/kg) or vehicle on mechanical allodynia: (A) at day 4; (B) day 7 and (C) day 14, respectively. Values represent the mean ± SEM. Difference from vehicle (Veh): *p < 0.05, **p < 0.01, ***p < 0.001, and #p < 0.05 Nox vs GBP.
Figure 2
Figure 2
Dose–effect relationship of Noxiall® (Nox) on CCI-induced mechanical allodynia at: (A) day 4 (B); day 7; (C) day 14. Animals were treated twice a day with Noxiall® at a high (PEA 300 mg/10 ml/kg, Myrrh 25 mg/10 ml/kg, BCP 5 mg/10 ml/kg, and Rosmarinus officinalis 6.16 mg/10 ml/kg); intermediate (PEA 150 mg/10 ml/kg, Myrrh 12.5 mg/10 ml/kg, BCP 2.5 mg/10 ml/kg and Rosmarinus officinalis 3.08 mg/10 ml/kg) low (PEA 100 mg/10 ml/kg, Myrrh 8.32 mg/10 ml/kg, BCP 1.66 mg/10 ml/kg, and Rosmarinus officinalis 2.04 mg/10 ml/kg) dose or vehicle (Veh). Values represent the mean ± SEM. Difference from vehicle **p < 0.01, ***p < 0.001, ## p < 0.01, ### p < 0.001 (300 vs 150 mg/kg), and oo p < 0.01 (150 vs 100 mg/kg). Where not indicated, differences with the vehicle were not statistically significant.
Figure 3
Figure 3
Dose–effect relationship of pregabalin (PGB) on CCI-induced mechanical allodynia at: (A) day 4 (B); day 7; (C) day 14. Pregabalin (30, 50, or 100 mg/10 ml/kg) or vehicle were given twice a day. Values represent the mean ± SEM. Difference from vehicle: *p < 0.05, **p < 0.01, ***p < 0.001, and ## p < 0.01 (100 vs 50 mg/kg). Where not indicated, differences with the vehicle were not statistically significant.
Figure 4
Figure 4
Effect of co-administration of an ineffective doses of Noxiall® (Nox) and of pregabalin (PGB) on CCI-induced mechanical allodynia at: (A) day 4; (B) day 7; (C) day 14. Noxiall® (PEA 100 mg/10 ml/kg, Myrrh 8.32 mg/10 ml/kg, BCP 1.66 mg/10 ml/kg and Rosmarinus officinalis 2.04 mg/10 ml/kg), pregabalin (30 mg/10 ml/kg) their combination (Nox + PGB) or vehicle (Veh) were given twice a day. Values represent the mean ± SEM. Difference from vehicle: **p < 0.01 and ***p < 0.001. Where not indicated, differences with the vehicle were not statistically significant.
Figure 5
Figure 5
Effect of oral treatment with Noxiall® (Nox) and GBP on CCI-induced heat hyperalgesia in male CD1 mice. Animals (n = 9/group) were treated twice a day with Noxiall® (PEA 300 mg/10 ml/kg, Myrrh 25 mg/10 ml/kg, BCP 5 mg/10 mL/kg and Rosmarinus officinalis 6.16 mg/10 ml/kg), gabapentin (100 mg/10 mg/kg) or vehicle on mechanical allodynia: (A) at day 4; (B) day 7; and (C) day 14, respectively. Values represent the mean ± SEM. Difference from vehicle (Veh): **p < 0.01 and ***p < 0.001.
Figure 6
Figure 6
Total distance traveled in the open field test. Total distance in centimeters (cm) of their respective tracks were combined and statistically analyzed to visualize any differences in ambulation. With respect to the vehicle, mice treated with Noxiall® or gabapentin did not show significant differences in the Open Field Maze (OFM) when total distance was measured. Data are expressed as the mean ± SEM.

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