Analgesia enhancement and tolerance prevention of morphine: beneficial effects of combined therapy with omega 3 fatty acids

ROMAÑUK CAROLINA BEATRIZ; MANZO RUBEN HILARIO; OLIVERA MARÍA EUGENIA; LAINO CARLOS HORACIO

Rosario-Santa Fe

Otro; 2° Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2012); 2012

Facultad de Farmacia-Universidad Nacional de Rosario

Introduction. Morphine, as the hydrochloride (HCl-MOR) or sulphate salts, is one of the most used analgesic drugs to control pain1. Long-term treatment develops tolerance, hyperalgesia2, and adverse effects such as body weight loss, constipation, nausea, vomiting, sedation, drowsiness and pruritus3. These events are the main cause for the withdrawal/failure of the treatment. It has been demonstrated that the dietary intake of omega-3 fatty acids (ω3, commonly found in fish oil) helps relieve pain in patients with inflammatory diseases and other painful conditions 4,5. Its use associated with MOR would allow improving the clinical effectiveness of MOR. However, the physicochemical properties of MOR or their salts are unfavorable for combined administration with ω3. Objectives. (i) To evaluate the analgesic effect (AE) of ω3 and MOR, as individuals and in combination (synergism) and their potential advantages in connection with the development of analgesic tolerance (AT) and weight loss. (ii) To develop a pharmaceutical composition containing MOR/ω3 in therapeutic concentrations, that can be used as a base to obtain oral formulations. Materials and methods. The AE and AT were studied in male Wistar rats using the Hot-plate Test (HPT) recording the time the rat takes to lick its legs or to jump from the surface (latency period). The non specific effect on locomotor activity in rats previously exposed to HPT (by means of the Open-field Test, OFT) and the body weight variation (BWV, calculated as the ratio of the animal weight at the beginning and at the end of each experiment) were evaluated in each trial. The groups and treatments are shown in table 1. MOR (obtained by neutralizing HCl-MOR with NH4OH) and fish oil (as a source of ω3) were used to develop the pharmaceutical composition. Results and discussion. Pure MOR crystals were obtained as a monohydrated zwitterion which was insoluble in the fish oil. The in situ salification with oleic acid allowed obtaining the MOR/ω3 composition (P20120100854). In G-ω3-MOR/ω3, an increase in the latency period compared to G-St-MOR and G-ω3-Sal was detected. This synergism is observed even at sub-therapeutic doses of MOR (1 mg/kg). On the other hand, in G-St-MOR/ω3, an AE statistically different from G-St-Sal was not produced and, AE was not observed in G-St-MOR/ω3, suggesting that the previous treatment with ω3 plays a role in increasing the AE. The pretreatment with ω3 reduces the effect on AT, showing respectively an increase of 323.5 and 90.6 % in AE for G-ω3-MORchronic and G-St-MORchronic, relative to G-St-Sal. Chronic treatment with MOR also resulted in BWV of -3.1% in G-St-MORchronic and -1.78 % in G-ω3- MORchronic. None of the treatments modified significantly the locomotor activity with regard to G-St-Sal. Thus, it can be concluded that the pharmacological effects observed were specific. Conclusions. An AE was observed with ω3 dietary intake. Its combination with MOR has a synergistic effect even if sub-therapeutic doses of MOR are used. The chronic use of this association reduces the effect of AT and of BWV. The MOR/ω3 composition obtained would make it possible the development of oral formulations, contributing to new therapeutic approaches with a better response and fewer adverse effects associated with the MOR treatment.