Enhanced analgesic effects of tramadol and common trace element coadministration in mice

Chronic pain is managed mostly by the daily administration of analgesics. Tramadol is one of the most commonly used drugs, marketed in combination with coanalgesics for enhanced effect. Trace elements are frequent ingredients in dietary supplements and may enhance tramadol's analgesic effect either through synergic mechanisms or through analgesic effects of their own. Swiss Weber male mice were divided into nine groups and were treated with a combination of the trace elements Mg, Mn, and Zn in three different doses and a fixed dose of tramadol. Two groups served as positive (tramadol alone) and negative (saline) controls. Nociceptive assessment by tail-flick (TF) and hot-plate (HP) tests was performed at baseline and at 15, 30, 45, and 60 min after intraperitoneal administration. Response latencies were recorded and compared with the aid of ANOVA testing. All three trace elements enhanced tramadol's analgesic effect, as assessed by TF and HP test latencies. Coadministration of these trace elements led to an increase of approximately 30% in the average pain inhibition compared with the tramadol-alone group. The most effective doses were 0.6 mg/kg b.w. for Zn, 75 mg/kg b.w. for Mg, and 7.2 mg/kg b.w. for Mn. Associating trace elements such as Zn, Mg, and Mn with the standard administration of tramadol increases the drug's analgesic effect, most likely a consequence of their synergic action. These findings impact current analgesic treatment because the addition of these trace elements may reduce the tramadol dose required to obtain analgesia.