Long-term analgesic effect of clodronate in rodents

Several studies have shown that treatment with bisphosphonates can reduce the pain associated with different painful diseases. In a previous study we demonstrated that in mice two bisphosponates, clodronate and pamidronate, had an antinociceptive effect under acute conditions not related to bone processes, after in vein (iv) or intracerebroventricular (icv) injection. The present study tested the time-dependent antinociceptive action of clodronate and pamidronate in comparison with that of acetylsalicylic acid (ASA) and morphine after iv and icv injection using the tail-flick test in acute and chronic treatment. The effects of clodronate on other measures of animal behaviour were also evaluated. In the tail-flick test, administration of clodronate iv produced an antinociceptive effect that was greater than that of ASA and statistically significant up to 16 h; pamidronate iv showed a significant antinociceptive effect for only 6 h. Clodronate and pamidronate icv showed an increase in tail-flick latency time that was significant and lasted for 16 and 6 h, respectively, while morphine produced an antinociceptive effect for 24 h. In the test we found significant differences between male and female mice in the latency time values but not in the length of the analgesic effect. In the chronic treatment paradigm, clodronate produced a significant increase of the tail-flick latency after the first injection. The analgesic effect increased up to 50% after 5 days of treatment. Significant analgesic effects were still present after 3, 7, and 14 days from the end of treatment. Clodronate did not produce any significant behavioural effects in the Rota-rod test, pentobarbital-induced sleeping time, and locomotor activity cage. These data indicate that clodronate presents a central and peripheral prolonged antinociceptive effect, without any behavioural side effects.