Synergism between tramadol and meloxicam in the formalin test involves both opioidergic and serotonergic pathways

This study was designed to evaluate the antinociceptive interaction of the tramadol–meloxicam combination in different proportions (tramadol + meloxicam in 1:1, 1:3, and 3:1 ratios), as well as the role of nitric oxide, opioidergic, and serotonergic pathways in the antinociceptive effect of the combination. The effects of individual drugs and fixed‐ratio combinations were assayed using the 3% formalin test in mice. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Tramadol (3.16–10 mg/kg, i.m.), meloxicam (3.16–17.8 mg/kg, i.m.), and tramadol–meloxicam combinations produced a dose‐dependent antinociceptive effect. ED₃₀ values were estimated for the individual drugs, and isobolograms were constructed. The tramadol + meloxicam 1:1 and 1:3 ratio combinations showed synergistic interactions while the 3:1 ratio produced additive effects. Naloxone (1 mg/kg, i.m.) or methiothepin (0.1 mg/kg, i.m.), but not L‐NAME (3 mg/kg, i.m.), prevented the antinociceptive effects of the combination. These data suggest that (1) the tramadol–meloxicam combination produces a functional synergistic interaction that involves both opioid and serotonin receptors, and (2) this combination may be a promising tool in pain management. Drug Dev Res 73: 43–50, 2012. © 2011 Wiley Periodicals, Inc.     

The synergistic interaction between rilmenidine and paracetamol in the writhing test in mice

The aim of the study was to ascertain antinociceptive effects of rilmenidine, a second-generation imidazoline-alpha-2-adrenoreceptor agonist, and to see whether rilmenidine was able to increase the analgesic effects of paracetamol in the writhing test in mice. An acetic acid (0.7%) solution was injected into the peritoneal cavity and the number of writhes was counted. The influence on locomotor performance was tested using the rotarod test. Rilmenidine, paracetamol, and rilmenidine–paracetamol fixed-ratio combinations produced dose-dependent antinociceptive effects. ED₅₀ values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical additive ED₅₀ value for the rilmenidine–paracetamol combination was 109.23 ± 35.05 mg/kg. This value was significantly greater than the observed ED₅₀ value which was 56.35 ± 20.86 mg/kg, indicating a synergistic interaction. Rilmenidine did not impair motor coordination, as measured by the rotarod test, at antinociceptive and higher doses.     

Isobolographic analyses of the gabapentin-metamizol combination after local peripheral, intrathecal and oral administration in the rat

This study was designed to evaluate the possible antinociceptive interaction between gabapentin and metamizol on formalin-induced nociception. Gabapentin, metamizol or a fixed dose-ratio combination of both drugs were assessed after local peripheral, intrathecal and oral administration in rats. Isobolographic analyses were employed to define the nature of the interaction between drugs. Gabapentin, metamizol and gabapentin-metamizol combinations yielded a dose-dependent antinociceptive effect when administered by the three different routes. ED30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED30 values for the combination estimated from the isobolograms were 21.11 +/- 1.17 microg/paw, 104.6 +/- 5.5 microg/rat and 78.8 +/- 5.5 mg/kg for the local peripheral, intrathecal and oral administration routes, respectively. These values were significantly higher than the experimentally obtained ED30 values which were 11.3 +/- 1.5 microg/paw, 36.8 +/- 3.1 microg/rat and 15 +/- 1.2 mg/kg indicating a synergistic interaction. Systemic administration resulted in the highest synergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically to reduce formalin-induced nociceptive behavior suggesting that this combination could be useful to treat inflammatory pain in humans.     

Synergistic effects between codeine and diclofenac after local, spinal and systemic administration

This study was designed to evaluate the extent of the antinociceptive interaction between codeine and diclofenac at the local, spinal and systemic level. The effects of individual and fixed-ratio combinations of locally, spinally or orally given codeine and diclofenac were assayed using the formalin test in rats. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Codeine, diclofenac and fixed-ratio codeine-diclofenac combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or systemically. ED(30) values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED(30) values for the combination estimated from the isobolograms were 422.2+/-50.5 microg/paw, 138.5+/-9.2 microg/rat, and 9.3+/-1.1 mg/kg for the local, spinal and oral routes, respectively. These values were significantly higher than the actually observed ED(30) values which were 211.1+/-13.6 microg/paw, 45.9+/-3.9 microg/rat, and 2.5+/-0.2 mg/kg, indicating a synergistic interaction. Systemic administration resulted in the highest increase in potency, being about fourfold, while spinal and local administration increased potency in two- and threefold, respectively. The fact that the highest synergism was observed after systemic administration suggests that the interaction is occurring at several anatomical sites. The results support the clinical use of this combination in pain management.     

Evaluation of the interaction between tramadol and diclofenac in several models of nociception in the rat

Diclofenac and tramadol are drugs widely used for the treatment of pain. However, side effects may limit their use. As both drugs produce side effects that are dose‐dependent, it seems appropriate to combine them in order to reduce the requirements for efficacy and, consequently, side effects. The purpose of this study was to evaluate the possible synergistic effect of these drugs in three experimental models of nociception in the rat. Dose‐response curves for diclofenac and tramadol were constructed in three models, thermal hyperalgesia, formalin, and hot plate. From these curves, ED₄₀ or ED₃₀ (according to the model employed) values were obtained and isobolographic analyses were carried out based on 0.5:0.5 proportions. Synergistic interactions were observed in the thermal hyperalgesia and hot plate models and an additive interaction was obtained in the formalin test. These results suggest a good therapeutic potential of this combination in the treatment of pain. Drug Dev Res 72: 391–396, 2011. © 2011 Wiley‐Liss, Inc.     

Synergic antinociceptive interaction between tramadol and gabapentin after local, spinal and systemic administration

The possible interaction between tramadol and gabapentin on formalin-induced nociception in the rat was assessed. Tramadol, gabapentin or a fixed-dose ratio combination of gabapentin and tramadol were administered peripherally, spinally and orally to rats, and the antinociceptive effect was determined in the 1% formalin test. Isobolographic analyses were used to define the nature of the interactions between drugs. Tramadol, gabapentin and tramadol-gabapentin combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or orally. ED30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED30 values for the combination estimated from the isobolograms were 126.8 +/- 11.1 microg/paw, 23.1 +/- 2.6 microg/rat, and 2.23 +/- 0.32 mg/kg for the local, intrathecal and oral routes, respectively. These values were significantly higher than the actually observed ED30 values which were 13.3 +/- 2.1 microg/paw, 8.1 +/- 0.6 microg/rat and 0.71 +/- 0.10 mg/kg, indicating a synergistic interaction. Although efficacy was not improved, local peripheral administration resulted in the highest increase in potency, being about tenfold. Spinal and systemic administration increased potency threefold. Data indicate that low doses of the tramadol-gabapentin combination can interact synergistically to reverse formalin-induced nociception and may represent a therapeutic advantage for clinical treatment of inflammatory pain.     

Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non‐opioid analgesics, namely nefopam, a centrally acting non‐opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo‐oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED₅₀ values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED₅₀ values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of nefopam at a non‐analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan‐induced tactile allodynia, the combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non‐analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.     

Comparative efficacy and safety of intravenous non-steroidal anti-inflammatory drugs in two animal models of pain

In this study, the antinociceptive activity of five non-steroidal anti-inflammatory drugs (NSAIDs) was determined in two animal models of different pain intensity and compared with their capacity to produce motor incoordination and death. Intravenous clonixine, diclofenac, dipyrone (metamizole), ketorolac, and piroxicam produced dose-dependent antinociception in the acetylcholine-induced writhing test with ED₅₀ values ranging from 14 (clonixine) to 205 (dipyrone) μmol/kg. The behavioral responses in the 55°C hot plate assay were also inhibited in a dosedependent manner, but significantly higher doses were required to display antinociceptive activity, the ED₅₀ values ranging from 116 (clonixine) to 2, 263 (dipyrone) μmol/kg. In the writhing test, the antinociceptive effects of NSAIDs were present at doses far below those producing toxic effects. In contrast, their ED₅₀ values against a more intense nociceptive stimulus approached those producing lethal effects so that the therapeutic ratios were very small, ranging from 1.3 (diclofenac) to 3.0 (dipyrone). The antinociceptive activity of the reference drug morphine is striking, since both types of nociceptive responses were eliminated at doses substantially lower than those producing death (therapeutic ratios of 502 and 121). Morphine exhibited the highest antinociceptive efficacy, followed by dipyrone, ketorolac, clonixine, and piroxicam. Diclofenac showed a more limited efficacy. These findings imply potential risks for patients treated iv with this class of drugs and suggest caution in the use of high doses of NSAIDs. Future development of injectable NSAID formulations should include a detailed analysis of adverse reactions following iv administration of high doses. © 1995 Wiley-Liss, Inc.     

The combination of naproxen and citral reduces nociception and gastric damage in rats

It has been shown that the association of non-steroidal anti-inflammatory drugs with plant extracts can increase their antinociceptive activity, allowing the use of lower doses and, thus, limiting side effects. Therefore, the aim of this study was to examine the effects of the interaction between naproxen and citral on nociception and gastric injury in rats. Naproxen, citral, or combinations of naproxen and citral produced an antinociceptive effect. The administration of naproxen produced significant gastric damage, but this effect was not obtained with either citral or the naproxen-citral combination. The ED₅₀ value was estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED₅₀ for the antinociceptive effect (423.8 mg/kg) was not significantly different from the observed experimental value (359.0 mg/kg); hence, the interaction between naproxen and citral mediating the antinociceptive effect is additive. These data suggest that the naproxen-citral combination interacts at the systemic level, produces minor gastric damage, and potentially has therapeutic advantages for the clinical treatment of inflammatory pain.     

Anti‐inflammatory and antinociceptive effects of tilifodiolide,isolated from Salvia tiliifolia Vahl (Lamiaceae)

Salvia tiliifolia Vahl (Lamiaceae) is used for the empirical treatment of pain and inflammation. The diterpenoid tilifodiolide (TFD) was isolated from Salvia tiliifolia. The in vitro anti‐inflammatory effects of TFD (0.1–200 µM) were assessed using murine macrophages stimulated with LPS and estimating the levels of pro‐inflammatory mediators for 48 h. The in vivo anti‐inflammatory activity of TFD was assessed using the carrageenan‐induced paw edema test for 6 h. The antinociceptive effects of TFD were evaluated using the formalin test and the acetic acid induced‐writhing test. The effects of TFD on locomotor activity were assessed using the open field test and the rotarod test. TFD inhibited the production of TNF‐α (IC₅₀ = 5.66 µM) and IL‐6 (IC₅₀ = 1.21 µM) in macrophages. TFD (200 mg/kg) showed anti‐inflammatory effects with similar activity compared to 10 mg/kg indomethacin. The administration of TFD induced antinociception in the phase 1 (ED₅₀ = 48.2 mg/kg) and the phase 2 (ED₅₀ = 28.9 mg/kg) of the formalin test. In the acetic acid assay, TFD showed antinociceptive effects (ED₅₀ = 32.3 mg/kg) with similar potency compared to naproxen (ED₅₀ = 36.2 mg/kg). In the presence of different inhibitors in the acetic acid assay, only the co‐administration of TFD and naloxone reverted the antinociceptive activity shown by TFD alone. TFD did not affect locomotor activity in mice. TFD exerts in vitro and in vivo anti‐inflammatory activity and in vivo antinociceptive effects.