Effects of Calcium Magnesium Softgels on morphine tolerance and dependence in mice

M. Rabbani, H.M. Sadeghi & S. Godarzi. Department of Pharmacology, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.

Opiate drugs such as morphine are widely used in the clinical management of pain. Their clinical usefulness is limited, however, by tolerance and dependence. There are some unpublished reports indicating that Calcium Magnesium Softgels (CalMg) could prevent morphine and cocaine withdrawal syndrome. In the present study, we investigated the effects of CalMg (containing 25 mg/kg of calcium and 50 mg/kg of magnesium) on the development of morphine tolerance and physical dependence in mice.

Male Syrian mice (n=6-8/group; 25-30g; Pasture Institute, Iran) were made tolerant and dependent to morphine by using subcutaneous injection (am and pm) of morphine in increasing dose (30, 45, 60, 90 mg kg-1) over a four days period. Naloxone (5 mg kg-1) challenge was made two hours after the last injection of morphine and the signs of withdrawal (jumping, standing on feet, fast breathing, sniffing) were recorded for 15 minutes (Rabbani et al., 2004). Tolerance was assessed based on loss of the antinociceptive effects of morphine (20 mg kg-1, s.c.), using the modified Haffner’s methods, the tail-pinch test (Takagi et al., 1996). Statistical analysis was performed using one-way ANOVA with an appropriate post-hoc test. In all comparisons, P<0.05 was considered significant. Data expressed as mean ±s.e.mean.

Acute injection of CalMg at 50 mg kg-1, significantly decreased the number of standing and jumping (Table 1, P<0.05). Similarly, co-administration of calcium and magnesium (made up to a similar molar concentration of the capsule) also decreased number of standing and jumping, however, calcium alone at 50 mg kg-1 was ineffective in blocking these signs of morphine withdrawal. The mean latency to pain was significantly increased by 11 and 12 fold after the administration of 25 and 50 mg kg-1 of CalMg, respectively.

Table 1. Effects of acute CalMg and calcium and/or magnesium on naloxone-precipitated withdrawal signs in morphine dependent mice.

The lack of protective effects by calcium or magnesium alone in preventing the morphine withdrawal signs indicates that these two ions should be present in combination at specific concentration in order to prevent the withdrawal signs. Further studies are required to define the exact mechanism of action of CalMg.

Rabbani, M. et al., (2004). Iranian J. Pharm. Res. 2, 109-114.
Takagi, H. et al., (1996). Jpn. J. Pharmacol. 16, 287–294.