Tramadol (TRM) and metamizol (MTZ) are drugs with complex mechanisms of action, extensively used in combination in pain management. In the present investigation we have evaluated the interaction between MTZ:TRM in the ethacrinic acid writhing test in rats. Dose-response curves (s.c.) were obtained for each drug individually, combined in fixed potency ratios (1:0.3, 1:1, 1:3), and for MTZ in presence of a fixed-dose of TRM (3.5 mg/kg). Interactions were analysed using isobolograms, interaction indexes (INT-I) and ANOVA. We used naloxone (1 mg/kg s.c.) to determine the opioid-component of the effects (ED80). Isobolograms demonstrated antagonism at the ED20, for 1:0.3 and 1:3 mixtures (p<0.01), whereas 1:1 was additive. At the ED50 and ED80 all combinations showed synergy. Fixed-dose experiments demonstrated that treatment (p<0.0001), dose (p<0.0001), and their interaction (p<0.0001) were statistically significant. Naloxone partially antagonized TRM (67%), but not MTZ; the percentage reversal of the combinations was directly related to the dose of TRM in the combination. The results show that the MTZ:TRM interaction on antinociception is synergistic or antagonistic depending on the level of effect. Synergy is demonstrated at 50% or higher levels, thus supporting the results obtained in humans by our group. Below the ED50 antagonism or additivity is present depending on the ratio of the combination. The mechanisms of the interaction remain unknown.

No abstract

In the present study, we report a synergistic interaction between acetylsalicylic acid (ASA) and caffeine (CAF) on the inhibition of nociception in a model of peripheral inflammation in rat; on the contrary no interaction have been found on anti-inflammatory effects and peripheral prostaglandin E2 (PGE-2) synthesis inhibition. Acute inflammation was induced by the subplantar injection of carrageenan into the right hind paw, and the effects of the drugs were evaluated from 0 to 5h. Nociception was assessed using the Randall & Selitto test, and the inflammatory response by plethismometry. Oral administration of ASA (10-400mg/kg) induced dose-related anti-nociceptive and anti-inflammatory effects. On the other hand, oral CAF administration (5-50mg/kg) did not show a dose-related inhibitory effect, neither on the inhibition of nociception nor on the inflammatory response. To analyze a possible interaction between both drugs a dose-response curve to ASA plus a fixed dose of CAF (5mg/kg) was obtained 3h after the injection of carrageenan, when the inflammatory pain peaked. A fixed dose of CAF was able to improve the anti-nociceptive, but not the anti-inflammatory, effects of ASA. We also assessed, by enzyme immunoassay, the effects of the combination on peripheral PGE-2 levels: CAF did not alter the inhibitory effect of ASA on PGE-2 synthesis. Our results corroborate the well-known clinical effects of combining ASA and CAF; on the other hand, we rule out that prostaglandin synthesis inhibition at peripheral sites would be the mechanism responsible of the adjuvant anti-nociceptive effect of CAF.

No abstract

Tramadol is effective in the management of mild to moderate postoperative pain, but its administration is associated with nausea and vomiting. Patients treated with tramadol, often receive dexamethasone as antiemetic. The aim of our investigation was to assess if the two drugs interact in a murine model of acute visceral pain. Using the acetic acid writhing test in mice, we assessed the antinociceptive effects of tramadol and dexamethasone (a glucocorticoid with antiemetic effect) administrated individually and in a 1 : 1 fixed ratio combination. Tramadol and dexamethasone induced a dose-dependent inhibition of the writhing response when administered individually, with ED(50) values of 2.9 [2.09-4.31, 95% confidence limit (CL)] mg/kg, and 0.13 (0.05-0.29, 95% CL) mg/kg, respectively. The ED(50) of the combination was 0.13 (0.01-0.29, 95% CL) mg/kg; the isobolographic and interaction index analysis revealed a synergistic interaction. The results suggest that the combination of tramadol and dexamethasone could be beneficial in the management of postoperative pain in humans.

No abstract

No abstract

In clinics, the use of drug-drug combinations in order to manage acute and chronic pain is well established. On the one hand, analgesics are staggered according to pain severity: mild, moderate, and severe pain, and thus patients should progress through this analgesic ladder depending on the pain relief obtained. On the other hand, analgesic adjuvants should also be added in order to reach analgesia using lower doses of the drugs (i.e., opioids) used, thus reducing the incidence of adverse side-effects. However, although there is precise categorization of analgesics within drug-drug combinations, these multimodal analgesic approaches are most of the times based on empirical instead of accurate experimental data. In such a way, tramadol (TRM) and paracetamol (PRC) have been revealed as analgesic drugs that would synergically interact with opioid drugs (1, 2). Furthermore, the combination of TRM and PRC is also a common multimodal analgesic strategy that has been shown to be effective and generally well tolerated in patients with moderate to severe pain (3). Accordingly, in the present study we attempted to characterize the combination of the major opioid fentanyl (FEN) with a tramadol:paracetamol (TRM:PRC) mixture, in order to examine whether the analgesic effects of the mixture would be enhanced together with a FEN-dosage reduction and the consequent diminution of opioid-related adverse effects (i.e., constipation). In addition, we evaluated the role of opioid receptors in such drug-drug interaction, since both TRM and PRC possess diverse and complex mechanisms of action, in which the modulation of the opioid system would be included (4 -6).First of all, we analyzed the antinociceptive effects of the individual drugs. Briefly, male Swiss CD1 mice (20 -25 g) housed under controlled standard conditions (12-h dark/light cycle, 22°C temperature and 66% humidity) were injected with one or a mixture of the following drugs: FEN (KernPharma, Barcelona, Spain); TRM (Grünenthal, Madrid, Spain); PRC (Bristol-Myers Squibb, Madrid, Spain); naloxone (Sigma-Aldrich, St. Louis, MO, USA); naltrindole and nor-binaltorphimine (nor-BNI) (Tocris Bioscience, Bristol, UK) subcutaneously 30 min before testing. Then, mice were injected intraperitoneally with an acetic acid solution (0.6% v/v, 10 ml/kg) and placed in a clear plexiglass cylinder to observe after 5 min the number of writhes (a single writhe is defined as a contraction of the abdominal wall together with the twisting of the trunk and hind limbs extension) in a 5-min period (6). The Institutional Committee on Animal Use and Care, in accordance with the International Association for the Study of Pain guidelines on ethical standards for investigation in animals, approved the protocol. As previously described, FEN and PRC Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain Received September 1, 2011; Accepted December 25, 2011 Abstract. Multimodal analgesic approaches to manage acute and chronic pain are commonly used in humans. Here, we attempted to characterize...