Synergistic interaction between fentanyl and a tramadol: paracetamol combination on the inhibition of nociception in mice.

Multimodal analgesic approaches to manage acute and chronic pain are commonly used in humans. Here, we attempted to characterize a synergistic interaction between fentanyl, tramadol, and paracetamol on the inhibition of nociception in a model of visceral pain in mice. The three-drug combined treatment displayed a potent synergistic antinociceptive effect, together with a significant reduction of gastrointestinal transit inhibition. Furthermore, selective µ- and κ-opioid receptor antagonists reversed these synergistic antinociceptive effects, thus suggesting a pivotal role of the opioid system. Overall, this study presents accurate pre-clinical data that might be useful to improve the clinical management of opioid-mediated analgesia.

Fentanyl-trazodone-paracetamol triple drug combination: multimodal analgesia in a mouse model of visceral pain.

Multimodal or balanced analgesia is commonly used in the management of acute and chronic pain in humans, in order to achieve the best analgesic/safety profile. Here, by using a model of visceral acute tonic pain, the acetic acid-induced writhing test of mice, we show a synergistic interaction between fentanyl, trazodone and paracetamol on the inhibition of nociception. First of all, once assessed that all drugs induced dose-related antinociceptive effects, they were mixed in fixed ratio (1:1) combinations and a synergistic drug-drug interaction was obtained in all circumstances. Thereafter, we assayed the effects of the triple combination of fentanyl-trazodone-paracetamol and it was demonstrated that they displayed a potent synergistic interaction on the inhibition of acetic acid-mediated nociception. Interestingly, drug dosage reduction permitted to reduce the incidence of possible adverse effects, namely exploratory activity and motor coordination, thus it was demonstrated that it improved the benefit/risk profile of such treatment. Afterwards, we attempted to elucidate the mechanism of action of such interaction, by means of the non-selective opioid receptor antagonist naloxone. Interestingly, naloxone completely antagonized the antinociceptive effects of fentanyl, and it also partially reversed paracetamol and trazodone mediated analgesia. Furthermore, when naloxone was co-administered with the triple-drug treatment it blocked the previously observed enhanced antinociceptive effects of the combination. Thus, these results indicated that the endogenous opioid system played a main role in the present drug-drug interaction. Overall, the triple combination of fentanyl-trazodone-paracetamol induced a potent synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia.

Histamine H3 receptor activation potentiates peripheral opioid-mediated antinociception: substance P role in peripheral inflammation in mice.

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Adjuvant effect of caffeine on acetylsalicylic acid anti-nociception: prostaglandin E2 synthesis determination in carrageenan-induced peripheral inflammation in rat.

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.

Synergistic interaction between dexamethasone and tramadol in a murine model of acute visceral pain.

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.

Synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(alpha)-methylhistamine, on the inhibition of nociception and plasma extravasation in mice.

Here we report a synergistic interaction between fentanyl and the histamine H(3) receptor agonist R-(alpha)-methylhistamine on the inhibition of nociception and plasma extravasation in mice. Chronic inflammation was induced by subplantar injection of Complete Freund's Adjuvant into the right hind paw, and the effect of the drugs was evaluated 7 days later. Nociception and plasma extravasation were assessed by hot-plate and Evans blue tests respectively. Subcutaneous administration of fentanyl (0.01-0.1 mg/kg) induced dose-related anti-nociceptive and anti-extravasation effects (E(max)=100% and 62%, respectively). R-(alpha)-methylhistamine administration (0.3-3 mg/kg) showed a dose-related inhibitory effect on extravasation (E(max)=65%) but not on nociception. To analyze possible interaction between these two drugs, a dose-response curve to fentanyl plus a fixed dose of R-(alpha)-methylhistamine (0.5 mg/kg) was obtained. The dose-response curve for the combined treatment showed a shift to the left compared with that for fentanyl alone. Our results confirm that fentanyl and R-(alpha)-methylhistamine interact in a synergic way, inhibiting nociception and plasma extravasation.

Anti-exudative effects of opioid receptor agonists in a rat model of carrageenan-induced acute inflammation of the paw.

We evaluated the anti-exudative effects (Evan's blue) of mu-, delta- and kappa-opioid receptor agonists in a rat model of carrageenan-induced acute inflammation. The contribution of different components was assessed after the administration of: cyclosporine A, capsaicin, 6-hydroxydopamine, compound 48/80, and specific histamine-receptor antagonists. The results show that the mu-opioid receptor agonists morphine and fentanyl and the delta-opioid receptor agonists DPDPE (enkephalin, [D-Pen(2,5)]) and SNC 80 ((+)-4-[(alpha R)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide) decrease plasma extravasation in a dose-dependent manner, with a biphasic response. The effects were reversed by specific antagonists, and are predominantly mediated by peripheral opioid receptors. The integrity of sensory and sympathetic fibres is essential for the anti-exudative effects of fentanyl and DPDPE. Histamine and functional histamine H(2) and H(3) receptors are required for morphine and fentanyl (but not DPDPE) inhibition of plasma extravasation, suggesting different mechanism for mu- and delta-opioid receptor agonists. The present findings implicate multiple sites and mechanisms in the anti-exudative effects of exogenous opioids.

Non-steroidal anti-inflammatory drugs antagonise the constipating effects of tramadol.

We report an antagonistic interaction between tramadol and non-steroidal anti-inflammatory drugs (NSAIDs), on gastrointestinal transit in rats. Transit was evaluated with charcoal and results are expressed as %inhibition. Tramadol and morphine had ED(50)s of 120.70+/-9.54 and 3.20+/-0.26 mg/kg, respectively, while metamizol (85 mg/kg), paracetamol (100 mg/kg) or ibuprofen (50 mg/kg) had no effect. All combinations of tramadol plus an NSAID, resulted in a rightward, non-parallel shift of the curves, which showed (two-way analysis of variance, ANOVA) significant differences from tramadol alone for the dose (P<0.0001), the drug (P<0.0001) and their interaction (P<0.0001), demonstrating antagonism. No interaction was present for morphine plus NSAIDs. The results demonstrate that NSAIDs antagonise the constipating effects of tramadol in rats, a fact that could have clinical relevance when combinations of these drugs are used in pain management in humans.

Interaction between metamizol and tramadol in a model of acute visceral pain in rats.

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.