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Evidence for a pheripheral mechanism of action for the potention of the antinociceptive effect of morphine by dipyrone
Abstract
The potentiation of the antinociceptive effect of morphine by dipyrone (metamizol) and the possible participation of a peripheral mechanism on such synergism were studied with the use of the formalin test in the rat. Nociception was induced by the intraplantar injection of diluted formalin (1%) in the right hind paw. Local administration of either dipyrone or morphine in the site of injury produced a dose-dependent antinociceptive effect. When combined, noneffective doses of morphine (1.25 μg/paw) and dipyrone (100 μg/paw) produced a significantly greater antinociceptive effect compared with either drug alone or saline. The opioid antagonist naloxone partly reversed the effect of the dipyrone–morphine combination. On the other hand, the inhibitor of nitric oxide (NO) synthesis, NG-L-nitro-arginine methylester (L-NAME), but not its inactive isomer, D-NAME, completely antagonized the effect of the dipyrone–morphine combination. These results suggest that the potentiation of morphine-induced antinociception by dipyrone in the formalin test requires an important participation of local release of NO, activating the NO–cyclic GMP pathway at the peripheral level.
... On the other hand, the morphine – ketorolac combination has shown a significant synergism in the formalin, visceral nociception and neuropathic pain tests (Malmberg and Yaksh, 1993; Maves et al., 1994; Lashbrook et al., 1999). Moreover, acetylsalicylic acid significantly increased the antinociceptive effect of morphine in the hot-plate and formalin tests (Sandrini et al., 1998), whereas that local administration of dipyrone increased the peripheral antinociceptive effect of morphine in the formalin test (Bañuelos and Granados-Soto, 1999). Notwithstanding these observations, the information regarding the potential benefit of NSAID-opioid combinations yielding a rational basis for their use in clinical practice is still scarce. ...
... The first phase started immediately after administration of formalin and then diminished gradually in approximately 10 min. The second phase started at 15 min and lasted until 1 h ( Bañuelos and Granados-Soto, 1999). In the second phase of the formalin test, both codeine and diclofenac induced a dosedependent antinociceptive effect by the three studied routes of administration (Figs. ...
... In this study, by using a fixed-ratio strategy, isobolographic analysis demonstrated a significant synergistic interaction between codeine and diclofenac at peripheral, spinal and systemic levels. These results confirm previous experiments showing that coadministration of opioids and NSAIDs to rats produce an increased peripheral (Bañuelos and Granados-Soto, 1999), spinal (Malmberg and Yaksh, 1993) and systemic (Fletcher et al., 1997) antinociceptive effect compared with individual drugs. However, to our knowledge, this is the first report about the synergistic interaction between codeine and diclofenac in the rat at different levels of pain trans- mission. ...
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.
... One is the activation of the L-arginine/nitric oxide/ cyclic GMP (cGMP)/K + channel pathway, and the other is an interaction with the glutamatergic system. In this respect, it has been shown that N G -L-nitro-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, blocks dipyrone's antinociceptive effect in the formalin test (Aguirre-Bañuelos and Granados-Soto, 1999), and in a model of inflammation induced by prostaglandin E 2 (Lorenzetti and Ferreira, 1996). ATP-sensitive K + channel blockers prevent dipyrone's actions in a model of nociception induced by prostaglandin E 2 injection (Alves and Duarte, 2002), and calcium dependent K + channel inhibitors block dipyrone antinociception in rats injected with formalin (Ortiz et al., 2003). ...
... This effect persisted in both morphine-tolerant and rats repeatedly treated with dipyrone when they were switched to the morphine-dipyrone combination (Hernández-Delgadillo and Cruz, 2004). Although these studies clearly suggest that coadministration of dipyrone and morphine produces supra-additive effects, the mechanism of action involved in such synergism is not clear and the involvement of the opioid system is controversial (Taylor et al., 1998;Aguirre-Bañuelos and Granados-Soto, 1999). ...
... Analgesic potentiation has been reported for the combined administration of morphine and dipyrone in different models of antinociception, including arthritic inflammation (López- Muñoz, 1994;Hernández-Delgadillo et al., 2002), the formalin test (Aguirre-Bañuelos and Granados-Soto, 1999); the tail flick test (Carlsson and Jurna, 1987;Hernández-Delgadillo et al., 2003), and the writhing reflex test (Taylor et al., 1998;Miranda et al., 2005). Some attempts have been made to determine the mechanisms underlying this potentiation, leading to different results for each particular model. ...
The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.
... Lorenzetti and Ferreira initially showed that the local injection of dipyrone in rat paws inhibited carrageenan-induced inflammatory hyperalgesia, without anti-edematogenic effects; dipyrone, similarly to morphine, directly blocked ongoing hyperalgesia induced by PGE 2 and isoprenaline, suggesting a direct effect upon PSN excitability [81]. The role of the NO-cGMP pathway in the mechanisms of action of dipyrone was suggested because NOS and sGC inhibitors prevented dipyrone-mediated analgesia [83]; furthermore, a selective inhibitor of nNOS prevented dipyrone-mediated antinociception [136]; finally, the local antinociceptive effects of dipyrone were abolished by pre-treatment with NOS inhibitors [137]. Exploring the molecular mechanisms of dipyrone peripheral analgesia, Sachs et al. (2004) demonstrated the relevance of opening K + ATP channels via stimulation of PKG [119]. ...
... The involvement of the NO pathway in the peripheral analgesic actions of other drugs and endogenous substances has also been extensively investigated. There is evidence that peripheral cannabinoids (a CB1-dependent effect), PPAR-γ agonists, xylazine, hormones such as estradiol and melatonin, bovine lactoferrin, choline (via alpha-7 nicotinic receptors), hydrogen sulfide releasing drugs, phosphodiesterase inhibitors, and pertussis toxin engage the NO-cGMP signaling to promote peripheral antinociception in various experimental models of inflammatory pain [81,83,137,138,[149][150][151][152][153][154][155][156][157][158]. In addition, not only did these analgesic drugs and endogenous substances elicit peripheral analgesia through the activation of the NO pathway, but there was also compelling evidence that alternative therapies such as electroacupuncture and natural products (e.g., plant extracts, venoms, and toxins) also required the integrity of this pathway to exert peripheral analgesia [152,[159][160][161][162][163][164][165]. ...
... On the other hand, our results with morphine are in line with previous reports showing that local peripheral injection of morphine reduces the inflammatory phase of the formalin test [3,10,30,49]. There is evidence that the antinociceptive effect of morphine after peripheral local injection is reversed by opioid receptor antagonists [1,30] suggesting that the effect is mediated by opioid receptors present in the nociceptive peripheral terminals [30,37,45]. Contrary to our results, in which morphine did not reduce phase 1 of the formalin test, several reports have found that morphine reduces both phases of this test [14,29,42]. ...
... This pathway may also participate in the observed synergistic interaction in the present study as previously described for diclofenac [33,48] and morphine [15]. Accordingly, some authors have proposed that the NO-cyclic GMP pathway participates in the synergistic antinociceptive effect between morphine and dipyrone at the peripheral level [1]. ...
Background:
Combinations of non-steroidal anti-inflammatory drugs with opioids are frequently used to reduce opioid doses required in the clinical management of acute pain. The present study was designed to evaluate the possible antinociceptive interaction between morphine and diclofenac at peripheral level in male rats.
Methods:
Drugs were chosen based on their efficacy in the treatment of this kind of pain and as representative drugs of their respective analgesic groups. For the formalin test, 50 μ of 1% formalin solution was injected subcutaneously into the right hind paw. The interaction between morphine and diclofenac was evaluated by using isobolographic analysis and interaction index. Drug interaction was examined by administering fixed-ratio combinations of morphine-diclofenac (1 : 1 and 3 : 1) of their respective ED30 fractions.
Results:
Diclofenac and morphine reduced flinching behavior in a dose-dependent manner during phase 2 but not phase 1 of the formalin test. Isobolographic analysis showed a synergistic interaction for the combination of morphine and diclofenac after local peripheral administration.
Conclusions:
Data suggest that the combination of morphine with diclofenac at the site of injury is synergistic and could be useful in the treatment of wounds, bruises, rheumatisms and other painful peripheral conditions associated with an inflammatory process.
... Besides the role of nitric oxide in nociceptive pathways, several lines of evidence have indicated that NO induces analgesia ( Table 1) and also that it mediates the peripheral and central antinociceptive effect of analgesic compounds, such as opioids, non-steroidal anti-inflammatory drugs and natural products [49][50][51][52][53][54][55][56][57][58][59][60][61][62] (Table 2). ...
... Ach, acetylcholine; PPAR-c, peroxisome proliferator activated receptors. the a 2 -adrenoceptor agonist xylazine, hormones such as estradiol and melatonin, bovine lactoferrin, the anesthetic gas nitrous oxide, isosorbide dinitrate spray, hydrogen sulfide releasing drugs and phosphodiesterase inhibitors [50,51,[54][55][56][57][58][116][117][118][119][120][121][122][123][124]. In most of the studies referred above, the involvement of the NO-cGMP pathway in the antinociceptive effect of the analgesics was demonstrated by the use of NO synthase inhibitors, as well as of guanylyl cyclase inhibitors, administered in doses that display only peripheral (local) effects. ...
Nitric oxide (NO) is involved in many physiological processes and several lines of evidence have indicated that NO plays a complex and diverse role in the modulation of pain. Nitric oxide is an important neurotransmitter involved in the nociceptive process and, in the dorsal horn of the spinal cord, it contributes to the development of central sensitization. On the other hand, experimental data have also demonstrated that NO inhibits nociception in the peripheral and also in the central nervous system. In addition, it has been shown that nitric oxide mediates the analgesic effect of opioids and other analgesic substances. The information included in the present review aims to present and analyze data about the dual effect of NO on pain transmission and control, the molecular mechanisms involved in these effects and also the potential use of nitric oxide in pain therapy.
... Among non-steroidal anti-inflammatory drugs, dipyrone (also known as metamizol) is widely used in Latin America, Germany and other European countries (Miralles et al., 1987;Garcia-Alonso et al., 1991) due to its high analgesic efficacy and good gastric tolerability (Patel et al., 1980;Rodriguez et al., 1994;Planas et al., 1998). Some pre-clinical reports have shown that, acutely, dipyrone enhances morphine-induced antinociception (Carlsson and Jurna, 1987;Lopez-Muñoz, 1994;Taylor et al., 1998;Aguirre-Bañuelos and Granados-Soto, 1999). In a recent work using an inflammatory nociception test, we found that the combination of morphine plus dipyrone produced analgesic potentiation not only in acutely treated rats, but also in animals that had been treated once a day for 12 days with this combination (Hernandez-Delgadillo et al., 2002) without producing an increase in constipation effects. ...
... There is a consensus that non-steroidal anti-inflammatory drugs improve the antinociceptive effects of opioids when both types of drugs are co-administered acutely (Grotto et al., 1965;Malmberg and Yaksh, 1993;Sandrini et al., 1998;Maves et al., 1994;Christie et al., 1999;Lashbrook et al., 1999). In particular, it has been demonstrated that dipyrone produces an acute enhancement of morphine-induced antinociception in several animal models of nociception (Taylor et al., 1998;Aguirre-Bañuelos and Granados-Soto, 1999;Carlsson and Jurna, 1987;Lopez-Muñoz, 1994). The effectiveness of the combination of opioids with non-steroidal anti-inflammatory drugs has also been long recognised by clinicians (Calimlim et al., 1976;Bentley and Head, 1987;Picard et al., 1997) and the World Health Organization, who, since 1986, recommends the use of these combinations as the final step of the analgesic treatment ladder (World Health Organization, 1986). ...
This work analyses the time course of tolerance development and antinociceptive potentiation throughout repeated co-administration of morphine (an opioid receptor agonist) plus dipyrone (a non-steroidal anti-inflammatory drug) in the tail-flick test. Male Wistar rats were i.v. injected with morphine (3.1 mg/kg), dipyrone (600 mg/kg) or the combination morphine/dipyrone twice a day for 5 days. Dipyrone produced antinociceptive effects with a trend towards tolerance development at the end of the treatment. Morphine was initially effective, but complete tolerance developed after its fifth administration. The combination of morphine plus dipyrone produced a significant potentiation and longer duration of antinociceptive effects. The antinociceptive efficacy of morphine and dipyrone co-administration gradually decreased after the sixth injection. An additional group of rats treated with dipyrone for 11 days developed complete tolerance after the 19th administration. These data suggest that repeated co-administration of morphine plus dipyrone results in a delay of tolerance development and in a potentiation of their individual antinociceptive effects.
... Among nonsteroidal antiinflamatory compounds, dipyrone (also known as metamizol) is widely used in many countries for pain management due to its high efficacy and good gastric tolerability (Patel et al., 1980;Rodriguez et al., 1994;Planas et al., 1998;Sanchez et al., 2002). Some preclinical studies have shown that dipyrone enhances morphine-induced antinociception when both drugs are acutely coadministered (Carlsson and Jurna, 1987;Lopez-Muñoz, 1994;Taylor et al., 1998;Aguirre-Bañuelos and Granados-Soto, 1999;Hernández-Delgadillo et al., 2002). Our group has recently reported that the morphinedipyrone combination produces antinociceptive potentiation evaluated in the tail-flick test and delays tolerance development throughout repeated administrations (Hernández-Delgadillo et al., 2003). ...
... According to Taylor et al. (1998), simultaneous i.p. administration of subeffective morphine and dipyrone doses resulted in antinociception potentiation in the writhing test. Moreover, Aguirre-Bañuelos and Granados-Soto (1999) showed that when these analgesics were coadministered at the same formalin injection site in rats, they produced significantly higher antinociception than that seen with either drug in the formalin test. Taken together, this evidence shows that antinociceptive potentiation between morphine and dipyrone occurs for a wide variety of noxious stimuli. ...
Coadministration of morphine and dipyrone produces acute and chronic antinociceptive potentiation in drug-naive rats. In this work, the effectiveness of the combination was determined in rats pretreated with morphine or dipyrone. Nine groups of male rats received (i.v.) 3.1 mg/kg morphine, 600 mg/kg dipyrone, or the morphine-dipyrone combination twice a day for five administrations (three groups per treatment). From the 6th to the 10th administration, one group out of each treatment continued without change, while the other two were switched to one of the other two possible treatments. In morphine-tolerant rats, morphine plus dipyrone produced a transient antinociceptive potentiation. In dipyrone-treated animals, this combination produced a long-lasting potentiation. In animals only treated with the combination, antinociception was clear since the beginning, although it decreased after the 6th injection. No cross-tolerance was seen between morphine and dipyrone. These data suggest that dipyrone potentiates morphine-induced antinociception in dipyrone-treated as well as in morphine-tolerant rats.
... The mechanisms of the analgesic effect of the pharmacological drugs used by us have been studied in some detail today. Analgin has been shown to cause an analgesic effect due to direct activation of endogenous opioid systems [20], potentiation of the action of endogenous opioids [21], as well as blocking the action of analgesics on the endings of nociceptive terminals [22,23]. Tramal activates opioid mu-receptors, and also inhibits the re-uptake of norepinephrine, enhances the effect of serotonin and facilitates the action of dopamine in brain neurons [24,25]. ...
... Its mechanism of action, although still not fully elucidated, is mainly attributed to inhibition of cyclooxygenases. In spite of being classified as a nonsteroidal anti-inflammatory drug, it displays little or no anti-inflammatory activity [2]. ...
Background
Dipyrone is a non-narcotic analgesic/antipyretic widely used in some countries but prohibited in others due to suspected risk of agranulocytosis. The primary goal of this study was to evaluate hematological alterations in healthy adult volunteers after treatment with dipyrone.
Methods
The study enrolled 30 healthy volunteers of both genders, aged 19–37 years. They received tablets containing 500 mg of dipyrone sodium to be used four times daily for 7 consecutive days. Before the first administration, arterial pressure was measured and blood was collected in order to evaluate hematological baseline parameters. On the 8th day after the beginning of treatment, the volunteers had their blood pressure assessed once more and underwent a second blood draw. Total and specific leukocyte counts, creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), erythrocytes, and platelets were quantitatively determined.
Results
No statistically significant difference was observed among total or specific leukocyte counts. Number of platelets, erythrocytes, hemoglobin, and hematocrit decreased after treatment. Diastolic pressure, mean arterial pressure (MAP), and urea concentration declined, while creatinine, AST, and ALT showed no significant alterations. It is noteworthy that, even for parameters that showed statistically significant changes, the highest and lowest values remained within the normal ranges.
Conclusions
Although dipyrone has historically been associated with agranulocytosis, leukocyte counts remained practically unchanged after oral administration of dipyrone. On the other hand, the present study adds evidence that dipyrone is able to produce statistically relevant decrease in number of platelets, erythrocytes, hemoglobin, and hematocrit in healthy adults, even after short-term treatment.
... Obwohl der Wirkmechansimus von Metamizol nicht bis ins Detail geklärt ist, scheint es sich bei diesem Wirkstoff vorwiegend um einen im ZNS wirk samen Prostaglandinsynthesehemmer zu handeln. Des Weiteren werden opioiderge Wirkmechanismen, eine Wirkung auf die Signalkaskade des L-Arginin/NO/cGMP/K + -Kanals sowie Interaktionen mit dem Glutamatsystem diskutiert (2,3,5,24,33). Da die periphere Prostaglandinsynthese nur wenig gehemmt wird, fehlen Metamizol die für die "klassischen" NSAIDs charakteristischen antiphlogistischen Wirkungen. ...
Zusammenfassung
Unzureichend behandelte Schmerzen führen zu negativen systemischen Effekten und unter Umständen zu einer massiven Störung des Allgemeinbefindens unserer Patienten. Aus diesem Grund sollte ein Schmerzbeurteilungsplan standardmäßig in die klinischen Abläufe eingebunden sein. Für Hund und Katze stehen validierte Schmerz - beurteilungspläne zur Verfügung. Im Rahmen einer fortschrittlichen Schmerztherapie ist das Prinzip der multimodalen Analgesie zu beachten. Dies bedeutet, dass verschiedene analgetische Wirkstoffgruppen miteinander kombiniert werden, die ihre Wirkung an unterschiedlichen Stellen des Schmerzentstehungs- und Schmerzleitungssystems entfalten. Neben Opioiden, nichtsteroidalen Antiphlogistika und Lo - kalanästhetika finden unter anderem α2-Rezeptor-Agonisten, Ketamin und Gabapentin Anwendung. Hinzu kommen diverse nichtpharmakologische Therapieformen.
... Peripheral as well as central effects are responsible for the potent analgesic efficacy (Mazario and Herrero, 1999;Vazquez et al., 2007). Opioidergic pathways (Tortorici et al., 1996) and inhibition of cyclooxygenase (COX)-3 (Chandrasekharan et al., 2002) seem to be the main mechanisms of action; the analgesic effect is comparable to that of opioids in humans (Hempel, 1986;Aguirre-Banuelos and Granados-Soto, 1999) and dogs (Richter et al., 2007;Tacke et al., 2008). Metamizole has been shown to be effective in controlling post-operative pain in dogs undergoing OHE (Imagawa et al., 2011). ...
... Pyrazoles constitute an important group of organic compounds that have been extensively studied due to their numerous biological activities. Accordingly, dipyrone (also known as metamizole) is a potent antipyretic and analgesic pyrazole derivative, with little anti-inflammatory activity (4), that is used in several countries. Nevertheless, several adverse effects, including agranulocytosis, have been associated with its use (5). ...
The objective of this study was to determine the effect of eight 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-carboxyamidepyrazoles (TFDPs) on rat body temperature and baker's yeast-induced fever. TFDPs or vehicle (5% Tween 80 in 0.9% NaCl, 5 mL/kg) were injected subcutaneously and rectal temperature was measured as a function of time in 28-day-old male Wistar rats (N = 5-12 per group). Antipyretic activity was determined in feverish animals injected with baker's yeast (Saccharomyces cerevisiae suspension, 0.135 mg/kg, 10 mL/kg, ip). 3-Ethyl- and 3-propyl-TFDP (140 and 200 μmol/kg, respectively, 4 h after yeast injection) attenuated baker's yeast-induced fever by 61 and 82%, respectively. These two effective antipyretics were selected for subsequent analysis of putative mechanisms of action. We then determined the effects on cyclooxygenase-1 and -2 (COX-1 and COX-2) activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) oxidation in vitro, on tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and on leukocyte counts in the washes of peritoneal cavities of rats injected with baker's yeast. While 3-ethyl- and 3-propyl-TFDP did not reduce baker's yeast-induced increases of IL-1β or TNF-α levels, 3-ethyl-TFDP caused a 42% reduction in peritoneal leukocyte count. 3-Ethyl- and 3-propyl-TFDP did not alter COX-1 or COX-2 activities in vitro, but presented antioxidant activity in the DPPH assay with an IC₅₀ of 39 mM (25-62) and 163 mM (136-196), respectively. The data indicate that mechanisms of action of these two novel antipyretic pyrazole derivatives do not involve the classic inhibition of the COX pathway or pyrogenic cytokine release.
... Therefore, an important participation of central mechanisms in the analgesic action of the drug has been suggested. 27 Based on this knowledge, we stated the hypothesis that dipyrone (metamizol) could be an intraoperative analgesic alternative for opioids in patients with low cardiovascular reserve because it could produce better cardiovascular stability (mainly blood pressure values) than fentanyl. In dogs undergoing hip replacement, the use of dipyrone had a marked opioid-sparing or even opioid-replacing effect. ...
In this study, the investigation of the intraoperative effects of dipyrone (metamizol) on heart rate (HR), mean arterial pressure (MAP) and analgesic efficacy in rabbits is described for the first time. This was carried out to evaluate the cardiovascular stability achieved using dipyrone compared with fentanyl. In this prospective study, 17 female New Zealand White rabbits were randomly allocated to either one of two groups: dipyrone/propofol (DP) or fentanyl/propofol (FP). Anaesthesia was induced in both groups using propofol to effect (4.0–8.0 mg/kg intravenously) until the swallowing reflex was lost for intubation. After induction, anaesthesia was maintained with continuous infusion of propofol 1.5–1.7 mg/kg/min intravenously. Analgesics were then injected in defined boluses of either dipyrone 65 mg/kg or fentanyl 0.0053 mg/kg. After surgical tolerance, defined as loss of the ear pinch reflex and loss of the anterior and posterior pedal withdrawal reflex, was achieved, two surgical procedures were performed. The surgical procedures (implantation of either a pacemaker or an electrocardiogram transmitter), both require a comparable level of analgesic depth. During and after surgery, clinical variables, such as MAP, HR, peripheral arterial oxygen saturation (SpO2) and end-tidal CO2 (Pe′CO2) were recorded simultaneously every 2 min. Eight time points were chosen for comparison: baseline, surgical tolerance (ST), values at 10, 20 and 30 min after reaching ST, values at the end of propofol infusion (EI) and data at 10 and 20 min after EI. Both FP and DP combinations provided effective anaesthesia and analgesia in rabbits. In both groups a significant decrease of HR and MAP was measured. The results of this study indicate that the non-opioid drug dipyrone produces similar analgesic and even better cardiovascular effects by trend in rabbits. Therefore we conclude that dipyrone in combination with propofol can be used as an alternative to FP for intraoperative analgesia.
... Many analgesic drugs potentiate the antinociception induced by morphine in several models of pain [31] . For example , in a model of visceral pain, metamizol treatment showed synergism with morphine analgesia [17]; with a similar effect, being obtained in the formalin test [1] . Moreover, the combination of morphine and diclofenac was shown to be synergistic in acute inflammatory pain [4]. ...
To enhance analgesia, the combinatorial use of analgesic drugs with proven efficacies is a widely-used strategy to reduce adverse side effects. The present study characterizes the antinociceptive interaction of intrathecal morphine co-administered with different NSAIDs using isobolographic analysis.Antinoceptive activity was evaluated using a model for acute visceral pain, the writhing test of mice. The possible involvement of opioid receptors in the mechanism of action of the intrathecal co-administration of morphine and NSAIDs was investigated using the non-selective receptor antagonist naltrexone. The study demonstrated a synergistic antinociception of intrathecal administered combinations of morphine with the following NSAIDs: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supra additive effect was obtained with very low doses of each drug and it appeared to be independent of the COX-1 or COX-2 inhibition selectivity of each NSAID and was not significantly modified by intrathecal naltrexone. The findings of the present work suggest that the combination of opioids and NSAIDs has a direct action on spinal nociceptive processing, which may be achieved via mechanisms that are independent of the activation of opioid receptors. The ineffectiveness of naltrexone to reverse the analgesic activity of opioids + NSAIDs combinations indicates that other complex pain regulatory systems are involved in this effect.
... It is used for fever control (Levy et al., 1995) and pain relief of different aetiologies (Rodríguez et al., 1994;Muriel-Villoria et al., 1995;Planas et al., 1998;Martínez-Martin et al., 2001). Dipyrone exerts its analgesic effects through several action mechanisms, among which the best described are cyclooxygenase-2 inhibition (Campos et al., 1999), delayed activation of the L-arginine/nitric oxide/cGMP/K+ channel pathway (Aguirre-Bañuelos and Granados-Soto, 1999;Alves and Duarte, 2002), activation of the descending inhibitory pain control system (Tortorici and Vanegas, 1994;Hernández and Vanegas, 2001), interaction with the glutamatergic system (Beirith et al., 1998), and release of endogenous opioid peptides (Vázquez and Vanegas, 2000;Hernández-Delgadillo and Cruz, 2006). ...
D-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/D-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200+/-20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg D-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, D-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The D-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to D-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.
... 1994;Lopez-Munoz et al.,. 1996 . It has been suggested that this property of diclofenac is due to the activation of a NO-cyclic GMP pathway in the periphery. In addition, there are reports that morphine can indeed activate the same pathway to produce Ž its antinociceptive effect Ferreira et al., 1991;Duarte et al., 1992;Granados-Soto et al., 1997;Aguirre-Banuelos . and Granados-Soto, 1999 . Therefore, it is likely that the morphine-like antinociceptive effect of diclofenac on the first phase could be due to the activation of the NO-cyclic GMP pathway, leading to direct blockade of inflammatory sensitization. ...
The antinociceptive activity of an inhibitor of phosphodiesterase 5, alone or combined with diclofenac, was assessed in the formalin test. Local administration of diclofenac produced a significant antinociception in both phases of the formalin test in female Wistar rats. In contrast, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3,4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, an inhibitor of phosphodiesterase 5) produced significant antinociception, only during the second phase of the formalin test. Non-effective doses of sildenafil (25-100 microg/paw) significantly increased the antinociceptive effect of an inactive dose of diclofenac (25 microg) in both phases of the test. The antinociception produced by the drugs alone or the combination was due to a local action, as its administration in the contralateral paw was ineffective. Since sildenafil is a potent and selective inhibitor of phosphodiesterase 5, our results suggest that this drug produced its antinociceptive activity, and increased that of diclofenac, probably through the inhibition of cyclic GMP degradation.
... In addition to inhibiting cyclooxygenase, diclofenac (22) and dipyrone (23) also downregulate sensitized peripheral pain receptors. In fact, dipyrone possesses anti-inflammatory-independent antinociceptive activity in the mouse formalin, hot-plate and tailflick tests that depends on peripheral and central sites of action (24), and has a significant antinociceptive effect even in the absence of an anti-inflammatory response (25). In patients undergoing third molar extraction, there are reports for (26) and against (27) a preemptive analgesic property of dipyrone or diclofenac. ...
The treatment of pain before it initiates may prevent the persistent pain-induced changes in the central nervous system that amplify pain long after the initial stimulus. The effects of pre- or postoperative intraperitoneal administration of morphine (2 to 8 mg/kg), dipyrone (40 and 80 mg/kg), diclofenac (2 to 8 mg/kg), ketoprofen (10 and 20 mg/kg), and tenoxicam (10 and 20 mg/kg) were studied in a rat model of post-incisional pain. Groups of 5 to 8 male Wistar rats (140-160 g) were used to test each drug dose. An incision was made on the plantar surface of a hind paw and the changes in the withdrawal threshold to mechanical stimulation were evaluated with Von Frey filaments at 1, 2, 6 and 24 h after the surgery. Tenoxicam was given 12 or 6 h preoperatively, whereas the remaining drugs were given 2 h or 30 min preoperatively. Postoperative drugs were all given 5 min after surgery. No drug abolished allodynia when injected before or after surgery, but thresholds were significantly higher than in control during up to 2 h following ketoprofen, 6 h following diclofenac, and 24 h following morphine, dipyrone or tenoxicam when drugs were injected postoperatively. Significant differences between pre- and postoperative treatments were obtained only with ketoprofen administered 30 min before surgery. Preoperative (2 h) intraplantar, but not intrathecal, ketoprofen reduced the post-incisional pain for up to 24 h after surgery. It is concluded that stimuli generated in the inflamed tissue, rather than changes in the central nervous system are relevant for the persistence of pain in the model of post-incisional pain.
... These studies clearly suggest that co-administration of metamizol and morphine has beneficial antinociceptive effects. However, the mechanisms of action involved in the antinociceptive potentiation induced by this combination are not clear and the involvement of the opioid system is controversial (Taylor et al., 1998; Aguirre-Bañuelos and Granados-Soto, 1999). Moreover, no studies have been made to determine the efficacy of this combination after repeated administrations and studies concerning the potential synergism of unwanted side effects are lacking. ...
This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P<0.001) and repeated administration (280+/-17 vs. 131+/-22 ua; P<0.001). Antinociceptive effect of morphine was reduced in chronically treated rats (39+/-10 vs. 18+/-5 au) while the combination-induced antinociception was remained similar as an acute treatment (298+/-7 vs. 280+/-17 au). Acute antinociceptive effects of the combination were partially prevented by 3.2 mg/kg naloxone s.c. (P<0.05), suggesting the partial involvement of the opioidergic system in the synergism observed. In independent groups, morphine inhibited the intestinal transit in 48+/-4% and 38+/-4% after acute and chronic treatment, respectively, suggesting that tolerance did not develop to the constipating effects. The combination inhibited intestinal transit similar to that produced by morphine regardless of the time of treatment, suggesting that metamizol did not potentiate morphine-induced constipation. These findings show a significant interaction between morphine and metamizol in chronically treated rats, suggesting that this combination could be useful for the treatment of chronic pain.
... The relative paucity of underlying mechanisms of antipyretic drugs in the literature may be related to the fact that pyrexia, per se, is a poorly understood phenomenon. Therefore, it remains to be determined if other proposed mechanisms of action for pyrazoles at the peripheral level, such as glutamate binding displacement (Beirith et al., 1998), and alterations in the nitric oxide-GMPc pathway (Lorenzetti and Ferreira, 1996;Aguirre-Banuelos and Granados-Soto, 1999) are also involved in the antipyretic effects of this compound. ...
The effect of novel pyrazolines, 3-methyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (MPCA) and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (PPCA) on body temperature and endotoxin-induced fever was investigated in mice. The subcutaneous (s.c.) administration of 1.5 mmol/kg dipyrone, MPCA or PPCA and the intracerebroventricular (i.c.v.) administration of 225 nmol dipyrone reduced basal rectal temperature. Intracerebroventricular administration of 225 nmol MPCA or PPCA did not alter basal rectal temperature. The administration of 0.15 mmol/kg (s.c.) or 25 nmol (5 microl) dipyrone (i.c.v.), MPCA or PPCA had no effect on basal rectal temperature, but reversed lipopolysaccharide-induced fever. These results suggest that MPCA and PPCA cause antipyresis, which is similar to that caused by dipyrone, and may be useful antipyretic agents.
... The usefulness of the electronic pressure-meter for the study of analgesia is illustrated by its ability to detect in rats the local effects of a standard COX inhibitor, indomethacin (32), and a direct blocker of hypernociception, dipyrone (33). The effect of dipyrone is mediated by the activation of the arginine/nitric oxide/cGMP pathway (34,35). ...
The objective of the present investigation was to compare the sensitivity of an electronic nociceptive mechanical paw test with classical mechanical tests to quantify the intensity variation of inflammatory nociception. The electronic pressure-meter test consists of inducing the hindpaw flexion reflex by poking the plantar region with a polypropylene pipette tip adapted to a hand-held force transducer. This method was compared with the classical von Frey filaments test and with the rat paw constant pressure test, a modification of the Randall and Selitto test developed by our group. When comparing the three methods, the electronic pressure-meter and the rat paw constant pressure test, but not the von Frey filaments test, detected time vs treatment interactions in prostaglandin E2 (PGE2)-induced hypernociception. Both methods also detected the PGE2-induced hypernociception in dose- (50-400 ng/paw) and time- (1-4 h) dependent manners, and time vs treatment interactions induced by carrageenin (25-400 microg/paw). Furthermore, the electronic pressure-meter test was more sensitive at early times, whereas the constant pressure test was more sensitive at later times. Moreover, the electronic pressure-meter test detected the dose-dependent antinociceptive effect of local indomethacin (30-300 microg/paw) and dipyrone (80-320 microg/paw) on carrageenin- (200 microg/paw) and PGE2- (100 ng/paw) induced hypernociception, respectively, and also detected the ineffectiveness of indomethacin (300 microg) on the effect of PGE2. Our results show that the electronic pressure-meter provides a sensitive, objective and quantitative mechanical nociceptive test that could be useful to characterize new nociceptive inflammatory mediators and also to evaluate new peripheral analgesic substances.
... The activation of the NO-cGMP system may also be involved in the synergy observed in the current experiments. The modulation of spinal antinociceptive activity through this pathway has been described for both types of drugs, and a cooperative effect between NSAIDs and MOR in this respect cannot be ruled out [1,2,7,12,21,29,44]. ...
The antinociception induced by the intrathecal coadministration of combinations of morphine with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen, piroxicam, metamizol, diclofenac and ketoprofen was studied by isobolographic analysis in the acetic acid writhing test of mice. The effective dose that produced 50% antinociception (ED(50)) was calculated from the log dose-response curve of intrathecally administered fixed ratio combinations of morphine with each NSAID. By isobolographic analysis, this ED(50) was compared to the theoretical additive ED(50) calculated from the ED(50) of morphine and of each NSAID alone. As shown by isobolograms, all the combinations were synergistic, the experimental ED(50)'s being significantly smaller than the theoretically calculated ED(50)'s. The results of this study demonstrate potent interactions between morphine and NSAIDs and validate the clinical use of the combinations of opioids and NSAIDs in pain treatment, even by the intrathecal route.
... Nociception was assessed using the formalin test (Dubuisson and Dennis, 1977;Aguirre-Bañuelos and Granados-Soto, 1999). The rats were placed in open Plexiglas observation chambers for 30 min to allow them to acclimate to their surroundings; then they were removed for formalin administration. ...
The local peripheral (subcutaneous) injection of phosphodiesterase 3 inhibitor trequinsin dose-dependently enhanced formalin-evoked flinching during late second phase of this test. Treatment with the nitric oxide synthase inhibitor N-L-nitro-arginine methyl ester or guanylyl cyclase inhibitor 1-H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed trequinsin-induced pronociceptive effect. Results suggest that the peripheral phosphodiesterase 3 may play an important physiologic role on inflammatory pain by controlling cyclic AMP levels and therefore the nociceptor threshold.
... This drug, however, was not able to completely block the formalininduced nociceptive behavior. These results confirm a limited antinociceptive efficacy of local metamizol (Lorenzetti and Ferreira, 1996;Aguirre-Bañuelos and Granados-Soto, 1999) and it supports a significant participation of a peripheral component in the action of this drug. The peripheral antinociceptive activity of metamizol could be due to its action as inhibitor of prostaglandin synthesis (Brune and Alpermann, 1983;Abbate et al., 1990;Campos et al., 1999) as well as to the modulation of the NO -cyclic GMP pathway (Granados-Soto et al., 1995;Lorenzetti and Ferreira, 1996). ...
The present work assessed the possible participation of K+ channels in the peripheral antinociceptive action of metamizol in the 1% formalin test. Ipsilateral, but not contralateral, local peripheral administration of metamizol produced a dose-dependent antinociception only during the second phase of the formalin test. K+ channel blockers alone did not modify formalin-induced nociceptive behavior. However, local peripheral pretreatment of the paw with charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K+ channel blockers, respectively), 4-aminopyridine and tetraethylammonium (voltage-dependent K+ channel inhibitors), but not glibenclamide or tolbutamide (ATP-sensitive K+ channel inhibitors), dose-dependently prevented metamizol-induced antinociception. The above results suggest that metamizol could open large- and small-conductance Ca(2+)-activated K+ channels, but not ATP-sensitive K+ channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K+ channels was also suggested, but since nonselective inhibitors were used, the data await further confirmation.
With the aid of a well-thought-out pain management plan, existing or expected pain conditions in animals can be treated in a targeted manner. For this purpose, analgesics can be chosen from different drug classes taking into consideration the type, intensity and duration of the pain events. A reasonable combination of available substances and their species-specific usage allows the clinician to work selectively against the development of pathological pain conditions. These principles not only apply to cats and dogs but also to other small animals presented to veterinary practices. This paper is meant to provide a reliable guide for further improvement of pain treatment in small animal practice and to facilitate the selection of a case-specific pain regimen.
Objective: This article presents the current knowledge of pharmacology and clinical effects of Metamizol (Dipyrone) in dogs, cats and rodents. In the last years Metamizol has experienced a revival especially in human medicine. For long times Metamizol was known as a weak analgesic with especially antipyretic effects. The pharmacological effects were unknown for a long time. Today it is proven that central and peripheral effects are responsible for the potent analgesic efficacy of Metamizol. Opioiderg pathways and inhibition of the cyclooxygenases are proved mechanisms for the effects of this drug. Metamizol also shows antipyretic, weak antiphlogistic, spasmolytic and anticonvulsive effects. The analgesic efficacy is comparable to that of opioids. The side-effect of hypotension after intravenous injection can be avoided by slow injection. Agranulocytosis was never seen in veterinary medicine until now and is a side effect with an incidence of only 0.008% in human medicine. The gastro-intestinal tolerance of Metamizol is very good. Conclusion and clinical relevance: This article shows that Metamizol is an analgesic which is also very effective and well tolerated in veterinary patients.
To determine the acute anti-nociceptive and the minimal alveolar concentration (MAC) sparing effects of metamizole sodiummonohydrate (dipyrone) in dogs for possible perioperative analgesia.
Two groups of seven adult dogs were used in two separate randomised, blinded, controlled, cross-over studies. In each study, each dog received metamizole 50 mg kg(-1) intravenously (IV) and placebo (saline 0.9%) IV.
Sevoflurane MAC was determined using the bracketing technique and electrical stimulation (50 V, 50 Hz, 10 milliseconds) at a thoracic limb, before treatment and 1 and 4 hours post treatment. In conscious dogs, thermal thresholds were determined by ramped contact heat at the thoracic wall. Mechanical thresholds (MTs) were measured by constantly rising force pressing against the radial bone. Thresholds were determined pre and 45, 75, 105, 135, 165, 195, 225, 255, 285, 315, 345, 375, 435, 495, 555, 615, 675, 735 minutes and 24 hours post treatment. Parametric data were analyzed by analysis of variance for repeated measurements and paired t-tests. Friedman test was used for nonparametric data. Level of significance was set to <5%.
Metamizole did not change MAC of sevoflurane significantly compared to baseline values [mean ± SD Vol%; 2.7 ± 0.5 (BL); 2.8 ± 0.6 (1 hour); 2.8 ± 0.4 (4 hours)] and placebo [2.8 ± 0.5 (BL); 2.9 ± 0.5 (1 hour); 2.9 ± 0.4 (4 hour)]. Metamizole caused a significant rise in % TE up to 105 minutes (66.5 ± 12.1%) and in MT up to 75 minutes (12.7 ± 5.0 N) compared to baseline (55 ± 10%; 7.9 ± 1.8 N). There were no significant differences between treatments.
Metamizole did not induce an anaesthetic sparing effect. In awake dogs metamizole induced only mild and short cutaneous anti-nociception. Metamizole as the sole analgesic drug in the perioperative periode is not recommended.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.
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. ED30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED30 values for the combination estimated from the isobolograms were 422.2±50.5 μg/paw, 138.5±9.2 μg/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 ED30 values which were 211.1±13.6 μg/paw, 45.9±3.9 μg/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.
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.
Many analgesics used in adult medicine are not licensed for pediatric use. Licensing limitations do not, however, justify that children are deprived of a sufficient pain therapy particularly in perioperative pain therapy. The treatment is principally oriented to the strength of the pain. Due to the degree of pain caused, intramuscular and subcutaneous injections should be avoided generally.
The basis of systemic pain therapy for children are non-opioids and primarily non-steroidal anti-inflammatory drugs (NSAIDs). They should be used prophylactically. The NSAIDs are clearly more effective than paracetamol for acute posttraumatic and postoperative pain and additionally allow economization of opioids. Severe side effects are rare in children but administration should be carefully considered especially in cases of hepatic and renal dysfunction or coagulation disorders. Paracetamol should only be taken in pregnancy and by children when there are appropriate indications because a possible causal connection with bronchial asthma exists. To ensure a safe dosing the age, body weight, duration of therapy, maximum daily dose and dosing intervals must be taken into account. Dipyrone is used in children for treatment of visceral pain and cholic. According to the current state of knowledge the rare but severe side effect of agranulocytosis does not justify a general rejection for short-term perioperative administration.
In cases of insufficient analgesia with non-opioid analgesics, the complementary use of opioids is also appropriate for children of all age groups. They are the medication of choice for episodes of medium to strong pain and are administered in a titrated form oriented to effectiveness. If severe pain is expected to last for more than 24 h, patient-controlled anesthesia should be implemented but requires a comprehensive surveillance by nursing personnel.
Ketamine is used as an adjuvant in postoperative pain therapy and is recommended for use in pediatric sedation and analgosedation.
Dipyrone, also known as metamizol, and tramadol are drugs that are widely used for the treatment of pain; however, side effects can limit their use. As dipyrone and tramadol produce side effects that are dose dependent, it seems appropriate to combine these drugs to reduce their dose requirements and, consequently, side effects. The purpose of this study was to evaluate whether dipyrone and tramadol produce antihyperalgesic effects in the thermal paw stimulation model in the rat, and whether there is a synergistic interaction between them. Using this model, dose-response curves were constructed for dipyrone (10–178 mg/kg, p.o.) and tramadol (1–32 mg/kg p.o.). From these curves, an ED50 value was obtained and isobolographic analyses were carried out based on 1:1 and 0.6:0.4 (dipyrone:tramadol) potency ratio proportions. When the proportion was 1:1, an additive interaction was obtained, whereas the 0.6:0.4 proportion showed a synergistic interaction. These results suggest a good therapeutic potential of this combination. Drug Dev Res 70:450–454, 2009. © 2009 Wiley-Liss, Inc.
Metamizole, a nonnarcotic analgesic, has been used to treat pain and fever for almost 90 years in some countries, while in others it is completely unknown or forgotten. It was synthesized by the German company Hoechst AG in 1920, and its mass production started in 1922. Metamizole remained freely available worldwide until the 1970s, when it was found that the drug poses a risk of causing agranulocytosis. Soon after that, metamizole was banned in the United States, Japan, Australia, and part of the European Union. However it is still widely used in some European countries, Turkey, Israel, India, Brazil, and Third World countries. Metamizole is available over-the-counter and remains one of the most popular analgesics in Bulgaria. The objective of this study is to review the pharmaceutical and pharmaco-toxicological aspects of the drug. In Part II, the clinical profile of the drug will be discussed.
There is evidence that B vitamins produce antinociception in animals. However, potentiation of NSAID-induced antinociception by B vitamins is unclear. The current study was designed to investigate the antinociceptive interaction between a mixture of B vitamins and either acetaminophen or metamizol. Acetaminophen (56–316 mg/kg), metamizol (32–178 mg/kg), and the mixture of B vitamins (32–178 mg/kg of thiamine, pyridoxine, and cyanocobalamin in a 100:100:1 proportion, respectively) or a combination of each drug with the B vitamins mixture was administered orally to female Wistar rats, and the antinociceptive effect determined in the formalin test. Isobolographic analyses were used to define the nature of the interaction between NSAIDs and B vitamins. Oral administration of either drug produced a dose-related antinociceptive effect. Isobolographic analyses revealed that both acetaminophen or metamizol and the B vitamins mixture interacted synergistically in the formalin test, suggesting that these two combinations could be useful in treating inflammatory pain states. Drug Dev. Res. 66:286–294, 2006. © 2006 Wiley-Liss, Inc.
This study presents the effect of an ethanolic extract of the whole plant of Synedrella nodiflora, a plant used in Ghana for the treatment of epilepsy and pain, in formalin-induced pain and acetic acid-induced writhing assay and the possible mode(s) of action of its analgesic action. For comparison, morphine and diclofenac were used as standard opioid and NSAID respectively. The ethanolic extract (100-1000 mg kg-1; p.o.) and morphine (1-10 mg kg-1; i.p.) dose-dependently decreased both phases of the formalin-induced nociceptive behavior. The antinociceptive effect of S. nodiflora (300 mg kg-1 p.o.) on the first and second phases of formalin induced pain was significantly blocked by caffeine but not by naloxone. In the acetic acid- induced writhing test, diclofenac and S. nodiflora significantly reduced the number of writhes dose dependently. Also, the effect of S. nodiflora (300 mg kg-1 p.o.) was blocked by caffeine (3 mg kg-1 i.p.) but the analgesic effect of diclofenac was enhanced significantly. The observed effects of caffeine on the central and peripheral analgesic effects of S. nodiflora in the formalin and acetic acid induced writhing suggest the possible involvement of adenosinergic mechanism(s).
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.
Morphine and lidocaine are known to influence the perception of pain. The present study sought to determine the influence of local administration of morphine on lidocaine-induced analgesia in morphine non-dependent (MND), morphine dependent (MD) and morphine withdrawal (MW) animals.
Adult male Wistar rats were divided into four groups: Control, MND, MD and MW rats. Lidocaine (0.5, 1 and 2%) and morphine (200, 400 and 800 µg) were injected in the plantar surface of the right paw. MD animals received chronic oral morphine (0.1, 0.2, 0.3 and 0.4 mg/ml in their drinking water) for 20 days. Twenty four hours before experiment, the animals in the MW group were deprived of morphine in their drinking water (physical dependence was observed by precipitating an abstinence syndrome with naloxone 2 mg/kg i.p.). Analgesia was assessed using hot-plate apparatus.
Morphine (400 µg) and lidocaine (2%) produce local analgesia in MND group. In MND rats, non-analgesic doses of each drug (200 µg morphine and 1% lidocaine) were used in combination and produced analgesia. In MD animals, all doses of lidocaine produced analgesia, while in MW animals, it failed to produce analgesia. In this situation, local administration of morphine could eventually influence the analgesic effect of lidocaine.
Opioid withdrawal is one of the most common problems in clinic. This study determined the analgesic effect of lidocaine in MW animals in which lidocaine had no analgesic effect. In this regard, local administration of morphine with combination of lidocaine could probably produce an effective analgesia.
Combined analgesic regimens produce sufficient analgesia by additive or synergistic effects, and reduce the total dose of analgesics and minimise adverse effects. We investigated the metamizole, paracetamol and morphine combination with respect to postoperative pain treatment in lumbar disc surgery.
After Ethics Committee approval and informed consent, 63 patients were allocated to three treatment groups; as Group paracetamol: paracetamol (1 g), Group paracetamol-metamizole: paracetamol (1 g) and metamizole (1 g), and Group placebo: no analgesic. All the patients received intravenous (i.v.) morphine with a patient-controlled analgesia device (PCA) as the rescue analgesic. Pain was assessed by the numerical pain rating scale (NRS, 0-3). Total morphine consumption at 24 hours, patient satisfaction and side effects were investigated.
NRS of Group paracetamol-metamizole was low at 15th min, 30th min and 1st hour, and the difference reached statistical significance at 30th min (p=0.033). Patient satisfaction at the same measurement times was high in this group. Total morphine consumption and side effects were not statistically different between the three groups.
Addition of metamizole to paracetamol along with iv morphine PCA offers an advantage over single iv morphine PCA and paracetamol, with respect to early postoperative pain treatment and patient satisfaction.
To evaluate the short-term cardiovascular effects of IV administration of dipyrone (metamizole) as an intraoperative analgesic during total IV anesthesia with propofol.
6 healthy female New Zealand White rabbits.
Anesthesia was induced with propofol (4.0 to 8.0 mg/kg, IV) and maintained with the same drug (1.2 to 1.3 mg/kg/min, IV). After induction, 3 doses of dipyrone (65 mg/kg each) were administered IV at 25-minute intervals. Before and for 10 minutes after each dipyrone injection, the following vascular and hemodynamic variables were recorded at the left common carotid artery every minute after the first injection: vessel diameter; peak systolic, minimum diastolic, end-diastolic, and mean blood flow velocities; mean volumetric flow; resistance and pulsatility indices; mean arterial blood pressure (MAP); heart rate; arterial oxygen saturation (SpO(2)); and end-tidal partial pressure of CO(2) (PETCO(2)). Echocardiography was performed after the second injection. The same variables were measured at the abdominal aorta (AA) after the third injection.
Dipyrone injections caused a significant, transient decrease in the resistance index at the AA. Also detected were a minor decrease in pulsatility index at the left common carotid artery and a minor increase in end-diastolic blood flow velocity at the AA. The MAP, heart rate, SpO(2), and PETCO(2) did not significantly change after injections. A comparison of HR and MAP after the first and third bolus injections revealed only minor changes.
Dipyrone used with propofol anesthesia in rabbits appeared not to significantly impair cardiovascular and hemodynamic function.
To enhance analgesia, combination of analgesics drugs of proven efficacy is a strategy which is accompanied by a reduction of adverse effects. The present study was undertaken to characterize the antinociceptive interaction of morphine with different non-steroidal anti-inflammatory drugs (NSAIDs) using isobolographic analysis and the writhing test of mice. One of the possible mechanisms of action of spinally administered morphine with non-steroidal antiinflammatory drugs was investigated using the DOR antagonist naltrindole. The study demonstrated a synergistic antinociception of spinal administered combinations of morphine with the following NSAIDs agents: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supraadditive effect seems to be independent of the selectivity of each NSAIDs to inhibit COX-1 or COX-2. The findings of the present work suggest that the combinations of opioids and non-steroidal anti-inflammatory drugs have a direct action on spinal processing of the nociceptive information, which may achieved by additional mechanisms independent of prostaglandin synthesis inhibition and/or activation of opioid receptors. The lack of effect of naltrindole to modify the analgesic activity of the combination of opioids and NSAIDs indicates that others pain regulatory systems are involved in this central action. Therefore, these combinations could be a viable alternative to clinical pain management, especially trough multimodal analgesia.
Nitric oxide (NO) plays pivotal roles in controlling physiological functions, participates in pathophysiological intervention, and is involved in mechanisms underlying beneficial or untoward actions of therapeutic agents. Endogenous nitric oxide is formed by three isoforms of nitric oxide synthase: endothelial, neurogenic and inducible. The former two are constitutively present mainly in the endothelium and nervous system, respectively, and the latter one is induced by lipopolysaccharides or cytokines mainly in mitochondria and glial cells. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.
The involvement of nitric oxide (NO), cyclic GMP and ATP-sensitive K(+) channels in the antinociceptive effect of ketorolac was assessed using the formalin test in the rat. Local administration of ketorolac in a formalin-injured paw produced a dose-dependent antinociceptive effect due to a local action, as drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with N(G)-L-nitro-arginine methyl ester (L-NAME, an NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) or glibenclamide (an ATP-sensitive K(+) channel blocker) prevented ketorolac-induced antinociception. However, pretreatment with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not block antinociception. Local administration of S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) was inactive by itself, but increased the effect of ketorolac. The present results suggest that the antinociceptive effect of ketorolac involves activation of the NO-cyclic GMP pathway, followed by an opening of ATP-sensitive K(+) channels at the peripheral level.
The effects of local application of a cream containing nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine (SNAP) or isosorbide dinitrate were studied in a rat model of incision pain. An incision was made in the plantar aspect of a hind paw and the cream was applied inside the surgical wound. SNAP (1-10%) or isosorbide (2.5-5%) reduced the incision allodynia as measured with von Frey filaments. Higher concentrations produced a smaller or no effect, but SNAP (30%) intensified the allodynia. Allodynia was also intensified by SNAP (5% or 30%) in rats pretreated with intraplantar 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 4 microg), a guanylate cyclase inhibitor. The effect of isosorbide (5%) was prevented by ODQ. The cream containing SNAP released 10- to 20-fold more nitrite than did isosorbide from a macrophage culture. We conclude that local application of drugs generating a low NO concentration reduces incision pain through activation of guanylate cyclase. Drugs generating high NO concentrations, however, intensify pain via a guanylate cyclase-independent mechanism.
Synergism has been used to obtain analgesia at doses at which side effects are minimal. In addition, it has been demonstrated that inhibition of cyclooxygenase-2 is responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to evaluate the antinociceptive interaction between the preferential COX-2 inhibitor, rofecoxib and morphine. Several combinations were evaluated using the pain-induced functional impairment model (PIFIR), a rat model of arthritic pain. Surface of synergistic interaction (SSI) analysis and an isobolographic method were used to detect the antinociceptive potency of the drugs, given either individually or in combination. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Male rats received orally morphine alone (10, 17.8, 31.6, 56.2 and 100.0 mg/kg), rofecoxib alone (3.2, 5.6, 10, 31.6, 56.2 and 74.0 mg/kg) or 12 different combinations of morphine and rofecoxib. Three combinations exhibited potentiation of antinociceptive effects (10 mg/kg of morphine with either 5.6, 10 or 31.6 mg/kg of rofecoxib), whereas the other nine combinations showed additive antinociceptive effects. The combination of morphine, 56.2 mg/kg (p.o.), and rofecoxib, 31.6 mg/kg (p.o.), produced the maximum antinociceptive effect (P<0.05). This combination caused gastric injuries less severe than those observed with indomethacin, i.e. it reduced ulcers and erosion formation. The synergistic antinociceptive effects of rofecoxib and morphine are important and suggest that combinations with drugs may decrease the side effects associated with the use of nonselective NSAIDs. Furthermore, the present results suggest that combinations containing opioid drugs and selective COX-2 inhibitors may have clinical utility in pain therapy.
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 (ED 80 ).
Isobolograms demonstrated antagonism at the ED 20 , for 1:0.3 and 1:3 mixtures ( p <0.01), whereas 1:1 was additive. At the ED 50 and ED 80 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 ED 50 antagonism or additivity is present depending on the ratio of the combination. The mechanisms of the interaction remain unknown.
The intraperitoneal administration of morphine, diclofenac, ketoprofen, meloxicam, metamizol, paracetamol and piroxicam induced dose-dependent antinociception in mice tested with the acetic acid writhing test. The isobolographic analysis of the simultaneous intraperitoneal administration of fractions of the ED50's of morphine with each nonsteroidal anti-inflammatory drug (NSAID) demonstrated the existence of a supra-additive interaction (synergy). The selective antagonist of micro -opioid receptors naltrexone partially reversed the supra-additive interactions to additive interactions; however, the combinations of morphine/metamizol and morphine/paracetamol were completely antagonized, resulting in subadditive interactions. The selective antagonist of delta-opioid receptors naltrindole failed to significantly attenuate the combinations of morphine with ketoprofen, meloxicam and piroxicam, but decreased the activity of the combinations of morphine with diclofenac, metamizol and paracetamol, transforming the interactions from supra-additive to additive. Nor-binaltorphimine was used to evaluate the involvement of kappa-opioid receptors. Nor-binaltorphimine did not modify the supra-additive interaction of morphine and NSAIDs and the additive interaction of the co-administration of morphine and metamizol. The synergy between morphine and NSAIDs could be related to different pathways of pain transmission, probably related to the different intracellular signal transduction mechanisms of action of opioid and non-opioid agents.
The development of COX-2 selective inhibitors has opened a new era of clinical investigation in NSAIDs. Discussion of the established concepts of inflammation and therapeutical uses of these drugs has changed the rationale for its clinical use and therapeutic labeling of these drugs. A comprehensive discussion across basic science and clinical areas involved in each of these concepts is presented. This led to a remarkable re-evaluation of our insights on their traditionally proposed mechanisms of analgesia, their side-effects, and the clinical indication of NSAIDs as "over the counter" pain killers. This may shift physicians toward a more rational use of this drug class.
The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.
The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K(+) channels (K(ATP)(+)). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-n-acetyl-d,l-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K(ATP)(+) opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E(2) (PGE(2), 100 ng) into the rat paw for 14 days. After cessation of PGE(2) injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. In this phase, glibenclamide (which specifically closes K(ATP)(+)) fully restored persistent hypernociception, as did injection of PGE(2). Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade of acute and persistent hypernociception by opening K(ATP)(+) via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/NO/cGMP/PKG/K(ATP)(+) pathway constitute a previously undescribed well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases.
Combinations of NSAIDs and opioids are currently employed for the treatment of moderate-to-severe pain in order to obtain an increased analgesic esponse, allowing the use of low doses of each agent, hence limiting side effects. There is active interest in developing combinations for oral adminstration. Therefore, we examined the antinociceptive activity of oral indomethacin and codeine, alone and incombination, in the formalin test in the rat. Both codeine and indomethacin, when given alone, produced a dose-dependent antinociceptive effect. ED30 values were 5.0 +/- 0.31 and 54.8 +/- 5.8 mg/kg for codeine and indomethacin respectively. Codeine-indomethacin combinations also produced a dose-dependent antinociceptive effect. The interaction between these two agents was characterized by isobolographic analysis using a fixed-ratio dosing strategy. Accordingly, the theoretical ED30 of the combination for a pure additive interaction, (i.e., that the combined effect is the result of the sum of the effects of the individual components), was 29.9 +/- 2.9 mg/kg. The observed ED30 for the codeine-indomethacin combination was 21.7 +/- 2.34 mg/kg. Comparison by the Student "t" test showed that there is no statistically significant difference (p > 0.05) between the observed and the theoretical DE30 values and thus a synergistic interaction is ruled out. We conclude that the indomethacin-codeine interaction is additive and does not result in analgesic synergism, unlike other combinations such as codeine-diclofenac. Our results show that, since not all the opioid-NSAID associations result in synergism, the individual components of a combination should be carefully selected, and that mechanisms of synergy may suggest actions of the NSAID partner not previously known.
Subcutaneous injection of formalin into the dorsal surface of the hindpaw evoked a two-phased flinching (phase 1:0-9 min; phase 2: 10-60 min) of the injected paw. Intrathecal administration of the nonsteroidal anti-inflammatory drugs (NSAID) produced minimal effects upon phase 1, but showed a significant, though submaximal, dose-dependent suppression of the phase 2 response. Ordering of i.t. potency was (ID50 in nmol): indomethacin (1.9) > or = flurbiprofen (2.1) > ketorolac (5.2) > or = zomepirac (5.9) > S(+)ibuprofen (16) > or = ibuprofen(racemic) (19) > acetylsalicylic acid (27) > acetaminophen (250) > R(-)ibuprofen (> 270) = 0. Intraperitoneal administration also produced a dose-dependent inhibition of phase 2, but only at doses which were 100 to 1000 times higher than those required to produce similar effects after i.t. injection. Intrathecal and i.p. dose-response curves showed similar distinct plateaus of maximum achievable inhibition (intrinsic activity) of the phase 2 behavior, ranging from 20 to 50% of the control response. Varying the time of drug injection reveals that injection 9 min after formalin yielded effects the same as those observed when the agent was given 2 min before formalin. Pretreatment at longer intervals indicated that the duration of the antinociceptive effect was between 3 to 6 hr after the i.t. injection. The i.t. injection of the highest doses of the several NSAID were without significant effect upon the 52.5 degrees C hot plate test. These studies indicate that NSAID have a powerful effect upon spinal nociceptive processing evoked by the s.c. injection of formalin.
The mechanism of action for the mild analgesics is controversial. While some have proposed that they inhibit prostaglandin synthesis in the central nervous system to interfere with nociceptive mediators in the brain, others have proposed that they act directly on nociceptive neural pathways to produce analgesia. This class of drugs also possesses antipyretic activity. We examined the antipyretic effect of one such drug, dipyrone, because this might elucidate the mechanism of its analgesic activity. In rats implanted with a femoral vein catheter and a cannula guide tube aimed towards the organum vasculosum laminae terminalis (OVLT) in the brain, an i.v. injection of 2 micrograms/kg interleukin-1 beta (IL-1 beta) produced a fever of 0.38 +/- 0.07 degrees C while an injection of 20 ng prostaglandin E1 (PGE) into the OVLT produced a fever of 1.18 +/- 0.18 degrees C. Dipyrone (25 mg/kg, i.v.) decreased the IL-1 beta fever but had no effect on the PGE fever. After pretreatment with the immunoadjuvant, zymosan, the IL-1 beta fevers were enhanced to equal those induced by PGE. Only 0.1 micrograms/kg, i.v. IL-1 beta raised body temperature by 1.20 +/- 0.10 degrees C. An increased dose of dipyrone (50 mg/kg, i.v.) was required to attenuate this IL-1 beta fever; however, the PGE fever remained unaffected by this treatment with dipyrone. Thus, dipyrone treatment blocks IL-1 beta fever where synthesis of prostaglandin is a crucial step in the febrile process, but it has no effect on PGE fever where synthesis is bypassed. This suggests that dipyrone, probably through its active metabolites, inhibits prostaglandin synthesis to induce antipyresis and, by analogy, analgesia as well.
Noxious cutaneous stimuli enhance spinal excitability. The behavioral correlate to this response is found in the rat formalin test, in which formalin injection into the hindpaw evokes signs of nociception (flinching and licking of the injected paw) with acute (phase 1) and delayed-hyperalgesic (phase 2) components.
The effect of intrathecal morphine (a mu agonist), U50488H (a kappa agonist), ST-91 (an alpha 2 agonist), L-PIA (an adenosine A1 agonist), and ketorolac (a nonsteroidal antiinflammatory drug, or NSAID), were examined in rats undergoing the formalin test. Spinal interactions between ketorolac and the mu, kappa, alpha 2, and adenosine A1 agonists were assessed using isobolographic analysis.
Morphine and ST-91 caused a dose-dependent suppression of phase 1 and phase 2 of the formalin test, while U50488H and L-PIA had little effect on phase 1, but caused dose-dependent depression of phase 2. Intrathecal ketorolac inhibited the phase 2 response, but had limited effect on phase 1. The isobolographic analysis revealed a significant synergy (with fractional dose ratios of less than 1) between ketorolac and morphine or ST-91 for phase 1 and phase 2, but only an additive interaction was found between ketorolac and L-PIA or U50488H.
These observations offer systematic support for the powerful interaction between NSAIDs and opioids and certain other analgesics in clinical pain states. These studies also demonstrate that spinal synergy is not a common property of all interactions. Thus, the NSAID synergy appears to occur with agents that exert a concurrent action both pre- and postsynaptic to the primary afferents.
Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 μmol/kg, and 2.6 and 1.2 μmol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 μmol/site, and 0.4 and 0.9 μmol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 μmol/kg, 2.2 μmol/paw, 0.4 μmol/site and 0.14 μmol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 μmol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, l-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the l-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin, interaction of ATP-sensitive K+ channels, GABAB receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
Prostaglandins are mediators of reperfusion hyperalgesia; their site of action may be in the periphery, in the central nervous system, or both. We have investigated whether prostaglandins play a role in the central nervous system during reperfusion hyperalgesia, by intracerebroventricular (i.c.v.) micro-injection of non-steroidal anti-inflammatory drugs (NSAID), to inhibit local prostanoid synthesis. We induced tail ischaemia in conscious rats by applying an inflatable cuff at the base of the tail. The cuff was released at the first signs of co-ordinated escape behaviour. Responses to a noxious thermal stimulus were assessed, by measuring tail flick latency following immersion of the tail in water at 49°C, prior to and immediately after release of the tourniquet. Tail flick latency decreased significantly following ischaemia, that is there was post-ischaemic reperfusion hyperalgesia. Intracerebroventricular micro-injection of NSAID prior to applying the tourniquet had no effect on the co-ordinated escape behaviour during ischaemia or on the tail flick latency after application of a sham tourniquet (uninflated cuff). However all the drugs abolished the hyperalgesia evident during reperfusion. Doses required to abolish hyperalgesia were 0.001 mg/kg indomethacin, 0.08 mg/kg dipyrone, 0.09 mg/kg ibuprofen, 0.2 mg/kg diclofenac sodium and 0.2 mg/kg paracetamol. These doses are 2–3 orders of magnitude less than those necessary to abolish reperfusion hyperalgesia when the same drugs are administered systemically. Our results indicate that the development of reperfusion hyperalgesia of the rat's tail depends on the synthesis of prostanoids within the central nervous system.
In a model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test), simultaneous administration of subanalgesic doses of metamizol (150 mg/kg) and morphine (0.2 mg/kg) resulted in a potent analgesia (19±1 vs. 2.3±0.8 writhes; P<0.05). While the analgesic effect of morphine (2 mg/kg) was antagonized by naloxone (1 mg/kg), the opioid antagonist did not reverse the analgesia induced by the combination of metamizol and morphine. Potentiation by metamizol was also observed as a bilateral decrease in stimulus-evoked c-Fos induction in superficial laminas (I–II) of the dorsal spinal cord after drug combination compared to single administration (66.5±2.2 vs. 80.7±4.2; P<0.05). Conversely, the number of nuclei immunostained with an antibody that recognizes all proteins of the Fos family was not modified by the same dose combination compared to single treatment (21.1±1.3 vs. 20.2±1.2). Furthermore, in a model of somatic pain consisting of peripheral thermal stimulation of the paws, simultaneous administration of metamizol (100–250 mg/kg) and morphine (0.5 mg/kg) failed to modify flexor reflex latency.
The effect of inhibition of nitric oxide synthesis and guanylate cyclase on the peripheral antinociceptive effect of morphine was assessed by using the formalin test in the rat. Saline, N(G)-monomethyl-L-arginine, a nitric oxide synthesis inhibitor (50 microg) and methylene blue, a guanylate cyclase inhibitor (500 microg), did not exhibit any antinociceptive activity. However, morphine (10 microg) produced a significant antinociceptive effect in phases 2a and 2b, which was reduced by pretreatment with either N(G)-monomethyl-L-arginine or methylene blue. These results suggest that the local administration of morphine induces antinociception by the activation of the L-arginine-nitric oxide-cGMP pathway.
The peripheral and central effects of some non-steroid anti-inflammatory drugs, aspirin, indomethacin, paracetamol and phenacetin were studied by comparing their intraplantar and intracerebroventricular effects on hyperalgesia induced by carrageenin injected into the rat paw. Hyperalgesia was measured by a modification of the Randall-Selitto test. The agents tested had antialgesic effects when given by any route. Their intraventricular administration enhanced the antialgesic effect of anti-inflammatory drugs administered into the paw. Previous treatment of one paw with carrageenin reduced the oedema caused by a second injection of carrageenin in the contralateral paw. In contrast, it had no effect on the intensity of hyperalgesia but shortened the time necessary for it to reach a plateau. Administration of a prostaglandin antagonist (SC-19220) in the cerebral ventricles, in the rat paw or in both sites, significantly inhibited the hyperalgesia evoked by carrageenin. The maximal hyperalgesic effect of intraplantar injections of prostaglandin E2 could be further enhanced by its cerebroventricular administration. It was suggested that carrageenin hyperalgesia has a peripheral and a central component and that the cyclo-oxygenase inhibitors used may exert an antialgesic effect by preventing the hyperalgesia induced by a peripheral and/or central release of prostaglandins.
We tested the hypothesis that activation of the nitric oxide (NO)-cGMP pathway is involved in the mechanism of two directly acting non-opiate peripheral analgesics, myrcene and dipyrone, using our modification of the Randall-Selitto test. The NO inhibitor, NG-monomethyl-L-arginine (50 micrograms/paw) and methylene blue (500 micrograms/paw) abolished the analgesic effect of dipyrone and myrcene. Dibutyryl cyclic adenosine monophosphate (DbcAMP) caused a dose-dependent hyperalgesia (20, 50 and 100 micrograms/paw). Only responses to low doses of DbcAMP were inhibited by the two analgesics. Pretreatment with MY5445 (50 micrograms/paw) resulted in potentiation of the effects of both analgesics. These results support our hypothesis that the sensitivity of nociceptors may be controlled by the balance between the levels of cAMP and cGMP. Stimulation of the NO-cGMP pathway is probably the common denominator for the mode of action of peripheral analgesics which block hyperalgesia directly.
Functional activity of polymorphonuclear neutrophils (PMN) is associated with the metabolism of Arachidonic Acid (AA) released from membrane phospholipids. In this study the in vitro effect of dipyrone, a non steroidal anti-inflammatory drug, on the production of AA metabolites through cyclooxygenase (CO) and lipoxygenase (LO) pathways by stimulated PMN has been investigated. PMN isolated by counterflow centrifuge elutriator were greater than 98% pure and viable. Metabolite production was evaluated by RIA of Thromboxane A2 (TxA2), Prostaglandin E2 (PGE2), Leukotriene B2 (LTB4) and Leukotriene C4 (LTC4) after PMN stimulation with calcium ionophore A 23187 (20 microM). The levels of beta-thromboglobulin (RIA) lower than 5 ng/ml allowed us to rule out activation of residual contaminant platelets. In these experimental conditions, in the absence of dipyrone the products (ng/10(6) cells) of AA metabolism were LTB4 (3.51 +/- 0.22), LTC4 (0.81 +/- 0.08), TxB2 (0.144 +/- 0.025) and PGE2 (0.150 +/- 0.017). Incubation with dipyrone induced changes of PGE2 and TXB2 production in a dose dependent fashion (r = 0.83 and r = 0.87, p less than 0.001), obtaining already at the lowest drug concentration (5 micrograms/ml) a significant inhibition (33 and 40% for TxB2 and PGE2 p less than 0.005). No significant changes of LTB4 and LTC4 production have been observed. The results of this study indicate that dipyrone relevantly affects CO metabolite synthesis by stimulated PMN at concentrations comparable to those reached in therapeutic use. The inhibition of PGE2 synthesis which is present in inflamed tissues and actively participates in inflammatory reactions, could contribute to the therapeutic anti-inflammatory action of dipyrone.
The effects of a non-narcotic analgetic methamizole and the calcium channel blocker verapamil on carrageenan hyperalgesia, release of beta-endorphin and synthesis of prostaglandin E2 (PGE2) were studied. It was found that a combined administration of analgin and verapamil prolonged the analgesic effect. Analgin stimulated release of beta-endorphin with the maximum coinciding in time with the peak of the analgesic effect. Against the background of the action of calcium ionophore A 23187 the combination of analgin with verapamil inhibited PGE2 synthesis more distinctly. The combination of these pharmacological agents is suggested to exert the effect both at different levels, central and peripheral, and on various cellular mechanisms involved in pain modulation.
This study examined a possible peripheral site of action of opioids in the modulation of the response to noxious pressure on inflamed tissue. Rats developed a unilateral localized inflammation upon injection of Freund's complete adjuvant into one hindpaw. 4-6 days after inoculation, intraplantar administration of mu, delta and kappa selective agonists [D-Ala2,N-methyl-Phe4,Gly-ol5]-en-kephalin (1 micrograms), [D-Pen2,5]-enkephalin (40 micrograms) and U-50, 488H (50 micrograms) produced marked antinociceptive effects in inflamed but not noninflamed paws. Equivalent doses applied systemically (s.c. and i.v.) were without effect. Dose dependency and stereospecificity of these effects were demonstrated using (-)- and (+)-morphine and (-)- and (+)-tifluadom. Furthermore, by use of (-)- and (+)-naloxone, dose-dependent and stereospecific antagonism was shown. Lastly, reversal of effects of [D-Ala2,N-methyl-Phe4,Gly-Ol5]-enkephalin, [D-Pen2,5]-enkephalin and U-50,488H by mu, delta and kappa selective antagonists D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, ICI 174,864 and nor-BNI, respectively, indicated that these agents interact with discriminable populations of receptors. These observations suggest that several selective opioid agonists can modulate responses to noxious pressure through a peripheral opioid receptor-specific site of action in inflammation and that these receptors possess distinguishable pharmacological characteristics resembling those of mu, delta and kappa receptors.
The intradermal injection of mu (morphine, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and morphiceptin), kappa (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneactemide) and delta ([D-Pen2.5]-enkephalin and [D-Ser2]-[Leu]enkephalin-Thr) selective opioid-agonists, by themselves, did not significantly affect the mechanical nociceptive threshold in the hindpaw of the rat. Intradermal injection of mu, but not delta or kappa opioid-agonists, however, produced dose-dependent inhibition of prostaglandin E2-induced hyperalgesia. The analgesic effect of the mu-agonist morphine was dose-dependently antagonized by naloxone and prevented by co-injection of pertussis toxin. Morphine did not, however, alter the hyperalgesia induced by 8-bromo cyclic adenosine monophosphate. We conclude that the analgesic action of opioids on the peripheral terminals of primary afferents is via a binding site with characteristics of the mu-opioid receptor and that this action is mediated by inhibition of the cyclic adenosine monophosphate second messenger system.
Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.) than oedema (180 mg/kg, i.p.) Dipyrone administered intraperitonially or intraplantarly was able to antagonise PGE2-, isoprenaline- and calcium chloride-induced hyperalgesia, effects which are not observed with non-steroid anti-inflammatory drugs. Systemic or local administration of dipyrone had no effect upon Db-cAMP-induced hyperalgesia while a centrally acting analgesic, morphine, given systemically, was highly effective. These results support our suggestion that the mechanism of action of dipyrone is different from that of classical non-steroidal anti-inflammatory drugs. Although the site of action is peripheral its analgesic effect does not derive from inhibition of the synthesis of prostaglandins but is exerted via direct blockade of the inflammatory hyperalgesia.
Pyrazolone and salicylic acid derivatives and the aniline derivative, paracetamol, are often classified as peripherally acting analgesic agents, while morphine is a centrally acting analgesic agent. Since indications exist that the non-opioid analgesic agents can also produce central effects, experiments were carried out on rats under urethane anaesthesia in which activity was recorded from single neurones in the dorsomedial part of the ventral nucleus (VDM) of the thalamus that was elicited by supramaximal electrical stimulation of nociceptive afferents in the sural nerve. In addition, activity was recorded in ascending axons of the spinal cord which was evoked by electrical stimulation of nociceptive afferents in the sural nerve. The substances studied were morphine, the pyrazolone derivatives, metamizol (dipyrone) and aminophenazone ('Pyramidon'), lysine acetylsalicylate, and paracetamol. All drugs were found to depress dose-dependently evoked activity in VDM neurones after intravenous (i.v.) injection. The ED50 of morphine in depressing evoked activity in VDM neurones is 0.05 mg/kg. Morphine also dose-dependently reduced activity in ascending axons of the spinal cord, the ED50 being 1.7 mg/kg. The ED50 of metamizol in depressing evoked activity in VDM neurones is 120 mg/kg, and that of aminophenazone is 22.7 mg/kg. The 2 ED50 values differ significantly. It has been found previously that metamizol increased nociceptive activity in some ascending axons and aminophenazone increased this activity in all ascending axons tested. The ED50 of lysine acetylsalicylate in depressing evoked activity in VDM neurones is 74 mg/kg. The drug did not reduce nociceptive activity in ascending axons of the spinal cord. The ED50 of paracetamol in depressing evoked activity in VDM neurones is 19.0 mg/kg. Paracetamol did not depress nociceptive activity in ascending axons of the spinal cord at a dose as high as 150 mg/kg administered by intraperitoneal injection. Naloxone (0.2 mg/kg i.v.) abolished the depressant effects of morphine but failed to reduce those of the non-opioid analgesic agents even at a high dose (1 mg/kg i.v.). Unlike morphine, the non-opioid analgesic agents did not completely block evoked activity in VDM neurones but only partially blocked their activation. The results suggest that the non-opioid analgesic agents tested can produce a central analgesic effect which, however, is weaker than that of morphine.
The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 micrograms) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 micrograms) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/kg) or into the PAG (10 micrograms) in the tail-flick test. Morphine (2 micrograms) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.
The pyrazolone derivative, metamizol (dipyrone), possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties. It is often classified as peripherally acting. To test the possibility that a central action of the drug contributes to its antinociceptive and analgesic effects, experiments were carried out in which the tail-flick response to radiant heat, flexor reflex activity in the tibialis anterior muscle and activity in ascending spinal axons evoked by stimulation of afferent C fibres in the sural nerve, and activity of neurones in the periaqueductal grey matter and the substantia nigra were assessed in rats. Metamizol administered by intraperitoneal (i.p.; 10, 20 and 40 mg/kg) or intrathecal (i.t.; 50 to 400 micrograms) injection to intact rats dose-dependently prolonged the tail-flick latency. Administration by i.t. injection to spinal rats was without effect. Intravenous (i.v.) injection of metamizol (140 mg/kg) reduced flexor reflex activity in intact animals, while an i.t. injection to spinal rats was ineffective at a low dose (100 micrograms) or enhanced the reflex activity at a higher dose (400 micrograms). Activity in ascending axons responding to afferent C fibre stimulation was mostly depressed by i.t. injection of metamizol (40, 80 and 140 mg/kg) in rats with an intact spinal cord. Ascending activity was increased by i.t. injection of the drug (100 and 200 micrograms) to spinal rats. Metamizol (140 mg/kg) i.v. increased the activity of neurones in the PAG and reduced that of neurones in the substantia nigra. Metamizol administered by microinjection into the PAG prolonged the tail-flick latency (15-100 micrograms) and depressed C fibre-evoked activity in ascending axons (100 micrograms). The results suggest that a central action is involved in the analgesic effect of metamizol and that this central action manifests itself by an activation of inhibition originating in the PAG.
I.d. injections (0.1 ml.) were made at different sites on the volar surface of the arm.
PROSTAGLANDIN release can be evoked from many tissues by physiological, pathological or mechanical stimulation1. In one of the accompanying articles Vane2 has demonstrated that prostaglandin synthesis by lung homogenate is blocked by anti-inflammatory acids. In the other, Smith and Willis3 have shown that prostaglandin production induced by the action of thrombin on platelets is also inhibited by these agents.The dog spleen releases large amounts of prostaglandins, identified as a mixture of PGE2 and PGF2a, when stimulated either by sympathetic nerve excitation, by adrenaline or by noradrenaline4-6. The release of prostaglandin can be reproduced consistently by repetition of the same stimulus and in much greater amounts than can be extracted from the tissues4,6. Therefore the release represents fresh synthesis of prostaglandins rather than mobilization from an intracellular reservoir.
Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.
Indomethacin, a typical cyclo-oxygenase inhibitor, acts as an analgesic by preventing the hyperalgesia induced by prostaglandins during inflammation. Analgesics of the dipyrone type directly block the sensitization of nociceptors. In the present investigation, the analgesic effect of diclofenac was compared with that of indomethacin in two algesimetric tests which permit discrimination between the two types of analgesic: the rat knee joint incapacitation and the rat paw hyperalgesia tests. The analgesics were given either pre- or posttreatment relative to the induction of hyperalgesia with carrageenin or prostaglandin E2. In both tests intraperitoneal pretreatment with indomethacin was equally or slightly more potent than diclofenac. Posttreatment with diclofenac was more effective than posttreatment with indomethacin. This was particularly evident in the paw hyperalgesia test in which posttreatment with indomethacin was not effective while diclofenac caused dose-dependent analgesia. When nociception was induced by PGE2 in both tests, the administration of indomethacin directly into the knee joint or rat paw had no effect while diclofenac continued to cause dose-dependent analgesia. Thus, diclofenac has a direct effect on ongoing hyperalgesia in addition to its ability to block cyclo-oxygenase. Naloxone and N-methyl-nalorphine did not affect diclofenac analgesia, thus indicating that the analgesic effect of the latter is independent of a central or peripheral opioid effect. Local administration of agents which inhibit the formation of nitric oxide (NG-monomethyl-L-arginine) or inhibit the activation of guanylate cyclase by nitric oxide (methylene blue) abolished diclofenac-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
Combinations of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to control pain in the perioperative period, yet there are no quantitative evaluations of the interaction between opioids and nonsteroidal antiinflammatory drugs during visceral nociception. This study evaluated the interaction between morphine and ketorolac during visceral nociception in the rat.
The pressor response to noxious colorectal distention (80 mmHg, 20 s) was evaluated in 29 male Sprague-Dawley rats and dose-response curves were determined for intravenous morphine, ketorolac and the mixture of morphine and ketorolac. The data were interpreted using an isobolographic analysis to establish the nature of the interaction.
Intravenous ketorolac alone (8-32 mg/kg) did not have a significant antinociceptive effect, whereas morphine alone (1-4 mg/kg) produced significant antinociception during noxious colorectal distention (dose yielding a 50% reduction in nociceptive response relative to baseline pressor response = 1.7 +/- 0.6 mg/kg). Isobolographic analysis of the antinociceptive interaction demonstrated a highly significant, naloxone-reversible potentiation of intravenous morphine by ketorolac in the rat during visceral nociception (P < 0.001).
Ketorolac is a powerful potentiator of morphine antinociception during visceral nociception in the rat. However, intravenous ketorolac alone did not demonstrate antinociceptive properties during colorectal distention, a model of acute visceral nociception without a major inflammatory component. These data suggest that ketorolac may have a central modulatory effect on opioid pharmacology and the synergistic effect may be separate from its peripheral antiinflammatory properties. This study encourages further basic as well as clinical evaluations of the improved antinociception provided by combination therapy of opioids and nonsteroidal antiinflammatory drugs.
Recent investigations have shown that non-steroidal antiinflammatory drugs (NSAIDs) may exert an antinociceptive effect when administered at or within the central nervous system (CNS). This might be due to the engagement of CNS substrates that support the analgesic effects of opiates, including the periaqueductal gray matter (PAG) and the rostral ventromedial medulla (RVM). The off- and on-cells of the RVM have been proposed to inhibit and facilitate, respectively, nociceptive transmission. Accordingly, upon heating of a rat's tail the tail-flick (TF) reflex occurs only after off-cells have decreased, and on-cells have increased, their activity. In the present study, i.v. administration (200 and 400 mg/kg) or PAG microinjection (25, 50, 100 and 250 micrograms) of dipyrone (metamizol) to lightly anesthetized rats caused a dose-related retardation of the heat-elicited off-cell pause, on-cell discharge and corresponding TF. Neuronal response and TF retained their mutual time relationship but shifted pari passu toward longer latencies. This antinociception was apparent already 5 min post-injection and reached a maximum in 50-60 min for i.v. administration and 30-35 min for PAG microinjection. These results confirm other authors' findings of the direct antinociceptive action of NSAIDs upon PAG, and provide the first evidence for a plausible involvement of RVM off- and on-cells in such antinociceptive effect.
Surgical trauma induces nociceptive sensitization leading to amplification and prolongation of postoperative pain. While preemptive analgesic treatment with numerous agents has been successful in experimental animals, results of human studies remain conflicting. The authors used a multimodal approach for preemptive analgesia before abdominal surgery: diclofenac and metamizole inhibit prostaglandin synthesis, thus influencing peripheral sensitization; epidural local anesthetics induce conduction block, epidural opioids inhibit nociceptive synaptic transmission, and metamizole induces descending inhibition. The interaction of these drugs might suppress spinal nociceptive sensitization and postoperative analgesic demand.
One hundred forty-two patients scheduled for major abdominal surgery were randomly assigned to one of three groups and studied prospectively. Epidural catheters in groups 1 and 2 were placed at interspaces T8-T10, the position of the catheter was confirmed by epidurography, and sensory testing after administration of 5 ml mepivacaine 1%. Group 1 received 75 mg intramuscular diclofenac, 1000 mg intravenous metamizole, 5.3 +/- 1 mg epidural morphine, and 15-20 ml mepivacaine 1% 85 +/- 41 min before skin incision. Epidural analgesia was maintained by injections of 0.1 ml.kg-1.h-1 mepivacaine 1%. Group 2 patients received the balanced analgesia regimen before wound closure (221 +/- 86 min after skin incision). Group 3 patients did not receive any study substances. General anesthesia was induced with 5 mg/kg thiopental and 2 micrograms/kg fentanyl and maintained with enflurane and nitrous oxide. Postoperative analgesia consisted of patient-controlled intravenous morphine over 5 days.
Median visual analog scale pain intensities were < 3 cm and did not differ among the groups. Morphine consumption per hour on postoperative day 2 was 0.8 +/- 0.1 mg/h (group 1) < 1.2 +/- 0.1 mg/h (group 2) = 1.1 +/- 0.1 mg/h (group 3) and cumulative morphine consumption (in mg) on the morning of day 5 was 95 +/- 9 (group 1) < 111 +/- 11 (group 2) < 137 +/- 10 (group 3).
A significant reduction of patient controlled analgesia requirements could be achieved by our preincisional balanced analgesia regimen compared to application before wound closure. The more distinct difference between patients receiving balanced analgesia and those in the control group is based on the analgesic action of the study substances, which lasted about 14 h.
The objective of this study was to investigate the site of action of dipyrone in rat paw prostaglandin-induced hyperalgesia. The intracerebroventricular (i.c.v.) injection of dipyrone had no effect on the hyperalgesic response to prostaglandins. In contrast, intraplantar (i.pl.) and intrathecal (i.t.) injections produced dose-dependent analgesic effects. The analgesia observed following the intraperitoneal (i.p.), i.t., i.pl. or combined i.t. and i.pl. administration of dipyrone was abolished by pretreating the paws with L-NMMA (a nitric oxide synthase inhibitor) or methylene blue (MB, an inhibitor of soluble guanylate cyclase). These results support the suggestion that dipyrone-mediated antinociception results from a combined spinal and peripheral effect in the primary peripheral sensory neuron via stimulation of the arginine/cGMP pathway.
Medullary off- and on-cells have been proposed to inhibit and facilitate, respectively, nociceptive transmission. Upon heating the tail in lightly anesthetized rats, the tail flick (TF) reflex occurs only after off-cells decrease and on-cells increase their activity. Dipyrone (DIP) microinjection (100 micrograms/0.5 microliter) into the periaqueductal gray (PAG) caused retardation in the off-cell pause, on-cell burst and corresponding TF. This effect was partly reverted by naloxone given i.v. (l mg/kg) or microinjected into PAG (5 micrograms/0.5 microliter). These results suggest that endogenous opioids are partly responsible for the central antinociceptive action of DIP, and that such action involves medullary off- and on-cells.
To determine whether dipyrone has an opiate-sparing effect in post-operative pain therapy compared with placebo during patient-controlled morphine therapy (PCA) and to compare the effects on analgesia and respiratory and coagulation parameters.
Randomized, observer-blind, parallel-group, placebo-controlled study.
Surgical intensive care unit of a university hospital.
106 adult patients who were to undergo abdominal or urological surgery under 90-min standardized inhalational anaesthesia were entered and 103 were included in the efficacy analysis (53 on dipyrone, 50 on placebo).
Preprogrammed PCA (0.03 mg morphine/kg per bolus) with either dipyrone (initially 2.0 g i.v. and 1.0 g/2 ml i.v. at 4, 8 and 16 h) or placebo (saline).
Cumulative morphine consumption was calculated automatically during PCA. Pain intensity and pain relief and the investigator's global assessments of efficacy and tolerability were recorded on five-point verbal rating scales. Vital signs, standard laboratory parameters, respiratory rate, partial pressure of carbon dioxide (PCO2) and of oxygen, partial thromboplastin time (PTT) and Quick values were recorded. Total consumption of opiates in the dipyrone group (median 31.6 mg) was significantly less (p = 0.00015) than in the placebo group (median 50.3 mg), while pain relief (area under the curve) AUC was the same for both PCA+dipyrone (median 4.1) and PCA+placebo (median 3.9). Global assessment of efficacy was good to excellent in more than 90% of cases in both groups. Vital signs, respiratory rate, PCO2, PTT and Quick did not differ between groups. Adverse events were mainly nausea and/or vomiting (dipyrone, n = 4; placebo, n = 1); 1 patient in the placebo group had bradycardia. Three serious adverse events were unrelated to study medication. In 1 patient, the PCA programme malfunctioned and had to be changed.
Concomitant administration of dipyrone with on-demand morphine (PCA) reduces opiate consumption while maintaining post-operative pain relief with a low incidence of side-effects.
To study the antinociceptive effects of metamizol in a rat model of ureteric calculosis. Subjects: Adult female Wistar rats (n = 40).
Metamizol was given i.p. 50-100 mg/kg, 3 times daily for 4 days for behavioural testing, and 25-100 mg/kg i.v. whilst recording peristalsis or dorsal horn neurons.
An artificial stone was induced in one ureter. In 3 separate groups of stone-implanted rats, behaviour was recorded continuously on video tape, ureteric peristalsis or the electrical activity of single nociceptive dorsal horn neurons with ureteric input was recorded under anaesthesia. Data were compared with analysis of variance.
Metamizol inhibited the behavioural visceral crises, the abnormal ureteric peristalsis and the activity of nociceptive dorsal horn neurons.
Metamizol has central antinociceptive effects on the pain produced by a ureteric stone, and an additional spasmolytic effect on the hyperperistalsis produced by the stone.
The ability of metamizol to inhibit cyclooxygenase-1 and cyclooxygenase-2 activities has been evaluated using different cyclooxygenase sources. Metamizol inhibited purified cyclooxygenase-1 and cyclooxygenase-2 with an IC50 of about 150 microg/ml. A similar IC50 value for cyclooxygenase-2 was obtained in lipopolysaccharide-activated broken murine macrophages. Consistent with these findings, molecular models of the complexes between cyclooxygenase-1 or cyclooxygenase-2 with 4-methylaminoantipyrine, the major active derivative of metamizol, suggested a common binding mode to both isoforms. In intact cells, however, the inhibition profiles were markedly different. The IC50 values of metamizol for cyclooxygenase-1 in intact bovine aortic endothelial cells (BAEC) cells and human platelets were 1730 +/- 150 microg/ml and 486 +/- 56 microg/ml, respectively. Inhibition of cyclooxygenase-2 activity in murine macrophages and primary human leukocytes activated by lipopolysaccharide yielded IC50 values of 12 +/- 1.8 microg/ml and 21 +/- 2.9 microg/ml, respectively. These data indicate that the IC50 values obtained with purified enzymes or disrupted cells cannot always be extrapolated to the cyclooxygenase inhibitory activity of nonsteroidal antiinflammatory drugs (NSAIDs) in intact cells. The data presented here also indicate that cyclooxygenase-2 inhibition could play an important role in the pharmacological effects of metamizol.
Dicker-non-steroidal anti-inflammatory agents on the formalin test in the rat
- R K S Lim
- F Guzman
- D W Rodgers
- K Goto
- C Braun
Lim, R. K. S., Guzman, F., Rodgers, D. W., Goto, K., Braun, C., Dicker-non-steroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263, 136–146.
Mode of analgesic action of dipyrone
- Lorenzetti
Mechanism of diclofenac analgesia
- Tonussi