Synergistic action between a synthetic cannabinoid compound and tramadol in neuropathic pain rats

Abstract

In the present study the interaction of cannabinoid, PhAR-DBH-Me [(R, Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-ylphenyl-acetate] and tramadol in two neuropathy models, as well as their possible toxic effects, was analyzed. The anti-allodynic effect of PhAR-DBH-Me, tramadol, or their combination, were evaluated in neuropathic rats. Furthermore, the effective dose 35 (as the 35 % of the anti allodynic effect) was calculated from the maximum effect of each drug. Moreover, the isobolographic analysis was performed to determine the type of interaction between the drugs. A plasma acute toxicity study was carried out to assess the hepatic, renal, and heart functions after an individual or combined administration of the drugs, as well as histology using the hematoxylin-eosin or Masson-trichome method. PhAR-DBH-Me, tramadol, and their combination produced an antiallodynic effect on spinal nerve ligation (SNL) and cisplatin-induced neuropathic pain in rats. Moreover, PhAR-DBH-Me and tramadol combination showed a synergistic interaction in neuropathic pain rats induced by SNL but not for cisplatin-induced neuropathy. On the other hand, changes in renal and hepatic functions were not observed. Likewise, analysis of liver, kidney and heart histology showed no alterations compared with controls. Results show that the combination of PhAR-DBH-Me and tramadol attenuates the allodynia in SNL rats; the acute toxicology analysis suggests that this combination could be considered safe in administered doses.

Combination Drug Therapy for the Management of Chronic Neuropathic Pain

“…In this study, the addition of JWH015 reduced the gastrointestinal side effects and conditioned place preference associated with morphine treatment [126]. In contrast, additive, but not synergistic, analgesic effects were observed with combination treatment with cannabidiol and tramadol in the streptozotocin-induced rat model of diabetic neuropathy [127] and with PhAR-DBH-Me and tramadol in a model of cisplatin-induced neuropathy [125]. Ultimately, despite preclinical evidence of the anti-nociceptive effects of cannabinoid receptor 1/2 (CB1/2) agonism and fatty acid amide hydrolase (FAAH) inhibition, translation of these preclinical findings into clinical data has been limited.…”

“…Preclinical evidence also supports further evaluation of the potential for combination therapy with cannabinoids and opioids in the treatment of NP [133]. Combination therapy with morphine and WIN55,212-2 in rats exposed to chronic constriction injury [124] and combination therapy with tramadol and PhAR-DBH-Me, a synthetic cannabinergic compound, in rats exposed to spinal nerve ligation [125] both led to synergistic analgesic efficacy. Similarly, JWH015, a cannabinoid 2 receptor agonist, and morphine treatment led to synergistic analgesic efficacy in models of post-operative pain (plantar incision) and spared nerve injury [126].…”

Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model

“…Additionally, morphine, when combined with WIN55212, produced synergistic analgesia in the formalin test, and GP1a, a CB2 receptor agonist, enhanced the analgesic effect of morphine in the carrageenan test [15]. In a more recent study, a synergistic antinociceptive effects of the cannabinoid agonist PhAR-DBH-Me and tramadol combination were reported on spinal nerve ligation but not cisplatin-induced neuropathy in rats [16].…”