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The objective of this study was to evaluate the analgesic efficacy produced by tramadol given by two different routes of administration in patients experiencing pain after removal of an impacted mandibular third molar under local anesthesia. A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were assigned into four groups of treatment, twelve subjects per group: Group A, tramadol 50 mg IM one hr before surgery; group B, tramadol 50 mg into the surgical site; group C, tramadol by both routes of administration, 50 mg IM one hr before surgery plus 50 mg into the surgical site; and group D, control. We evaluated intensity of pain and analgesic consumption as was requested. Demographic characteristics and variables describing the difficulty of the surgical procedure were similar between groups. The duration of the anesthetic effect was significantly longer in the groups where tramadol was injected into the surgical site (215 and 252 min). Administration of systemic and local tramadol (50 mg) suppressed the pain intensity values in comparison to the control group (p < 0.05). Also, tramadol in both routes of administration suppressed the pain intensity values in comparison to all groups (p < 0.05). A significant reduction in the consumption of ketorolac was seen in all treatments as compared to the control group. However, only in the route combination group was a significant reduction in the requirement of acetaminophen observed. Nine patients requiring additional medication were treated with ketorolac 30 mg injected intramuscularly; 2 in the systemic group, 2 in the local group, 4 in the control group and only 1 in the combination group. Adverse events were minimal and similar in all groups.

In vitro studies have suggested that arsenic can modify the activity of macrophages in the mouse producing an over-regulation of the COX-2 and increased concentrations of PGE2 in endothelial cells. These effects may lead in vivo to enhancement of inflammatory and painful responses. In this study we studied the effect of an acute intoxication with sodium arsenite (1, 5, 10, 36 and 100 nmol/kg s.c.) on the nociceptive response of mice in the formalin test. On the other hand, the effect of arsenic on the antinociceptive response mediated by tramadol was evaluated in mice administered with a single dose of the analgesic agent (10 mg/kg s.c.). Arsenic levels in the liver were measured as a marker of the intoxication degree. Our results indicated that the arsenic acute exposure increases the nociceptive behavior in mice in a dose-dependent manner. Accordingly, the exposure to arsenic partially blocked the analgesic effect of tramadol although no statistical differences were reached. These results support the previous in vitro evidences regarding the alterations in the inflammatory-painful processes produced by the acute exposure to arsenic. Moreover, our results suggest that the intoxication with arsenic might exacerbate the pathological state in inflammatory diseases.

Tramadol is an atypical opioid with a complex mechanism of action including the synergistic interaction between the parent drug and an active metabolite. However, the local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of locally (subcutaneous) and systemically (intraperitoneal) dosed tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In the second phase of the formalin test, tramadol was active not only by the systemic (ED50 7.15+/-0.46 mg/kg i.p.) but also by the local route (ED50 134.6+/-25.1 microg/paw). The isobolographic analysis evidenced a "self-synergism" in the antinociceptive effect between the two routes of administration since the experimental ED50 (30.8+/-0.1 "dose units") of the combination was significantly lower than the theoretical ED50 (70.9+/-12.6 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since naloxone reversed the potentiation. The observed site-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.