Innovative pharmacological treatment for enhancement of analgesia and prevention of morphine side effects based on a new pharmaceutical composition containing morphine combined with omega-3 fatty acids

Buenos Aires

Congreso; 15th World Congress on Pain-IASP 2014; 2014

IASP

Introduction. Chronic pain has a marked negative impact on quality of life. Morphine, as the hydrochloride (HCl-MOR), is one of the most used analgesic drugs to control pain. Long-term treatment develops tolerance, hyperalgesia, and adverse effects such as body weight loss, constipation, nausea, vomiting, sedation, drowsiness and pruritus. These events are the main cause for the withdrawal of the treatment. It has been demonstrated that the dietary intake of omega-3 fatty acids (O3, commonly found in fish oil) helps relieve pain in patients with inflammatory diseases and other painful conditions. 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 O3. Aim of Investigation. (i) To evaluate the antinociceptive effect (AE) of O3 and MOR, as individuals and in combination and their potential advantages in connection with the development of analgesic tolerance (AT), weight loss, and constipation. (ii) To develop a pharmaceutical composition containing MOR:O3 in therapeutic concentrations, that can be used as a base to obtain oral formulations. Materials and methods. MOR (obtained by neutralizing HCl-MOR with NH4OH) and fish oil (as a source of O3) were used to develop the pharmaceutical composition (MOR:O3). The AE was evaluated in groups of rats Wistar fed with standard diet or O3 supplemented diet, which were given: a) MOR subcutaneously (1, 2.5, 5, and 6 mg/kg), b) oral MOR (12 mg/kg) or its equivalent in composition MOR:O3. The AT was studied in similar groups of animals following the protocol described by Lilius et al., 2009. For both, the AE and AT, the Hot-plate Test (HPT) recording the time the rat takes to lick its legs or to jump from the surface (latency period) was used, and a saline solution was administered as control. The non specific effect on locomotor activity in rats previously exposed to HPT (by means of the Open-field Test), the body weight variation (BWV, calculated as the ratio of the animal weight pre- and post- each experiment) and, the constipation (percentage of intestinal distance moved by the charcoal from the pylorus to caecum) were evaluated in each trial. For each experiment, two-way analysis of variance (ANOVA) with treatment and diet as factors were performed. P < 0.05 was considered as statistically significant. Results and discussion. Pure MOR crystals were obtained as a monohydrated zwitterion which was insoluble in the fish oil. In order to get a stable solution of MOR in the fish oil, the addition of a salifying agent was needed, according to Laino 2012 (Argentine Patent Application P20120100854). In the supplemented diet group that received a dose of the MOR:O3, an increase in the latency period compared to the standard diet group + oral MOR and the supplemented diet group + saline solution was detected. This synergism is observed even at sub-therapeutic doses of MOR (1 mg/kg). On the other hand, in the standard diet group that received a dose of the MOR:O3, an AE statistically different from control group was not produced and, AE was not observed in the standard diet group + a dose of the MOR:O3, suggesting that the previous treatment with O3 plays a role in increasing the AE. Also, another beneficial effect of combined treatment after chronic administration was also observed, since MOR in combination with O3, can decrease the body weight loss and constipation produced by MOR. None of the treatments modified significantly the locomotor activity with regard to control group. Thus, it can be concluded that the pharmacological effects observed were specific. Conclusions. An AE was observed with O3 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 AT effect, the BWV and constipation. The MOR:O3 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. Acknowledgments This work was supported by SECyT-UNC, FONCyT, CONICET and SECyT-UNLAR.