Tramadol and M1 Bioavailability Induced by Metamizole Co-Administration in Donkeys (Equus asinus).

Our objective was to assess the pharmacokinetic characteristics of metamizole when administered together with tramadol in a single intravenous dose to donkeys. Ten male animals received 10 mg∙kg-1 of dipyrone associated with 2 mg∙kg-1 of tramadol (T2M10) and 25 mg∙kg-1 of dipyrone with 2 mg∙kg-1 of tramadol (T2M25). Venous blood samples were taken from groups to determine the pharmacokinetics after drug administration, using initial brief intervals that were followed by extended periods until 48 h. Restlessness and ataxia were observed in two animals in the T2M25 group. Analysis revealed prolonged detectability of tramadol, 4-methylamine antipyrine, 4-aminoantipyrine (up to 24 h), and O-desmethyltramadol (up to 12 h) after administration. Although metamizole and its metabolites showed no significant pharmacokinetic changes, tramadol and O-desmethyltramadol exhibited altered profiles, likely because of competition for the active sites of CYP450 enzymes. Importantly, the co-administration of metamizole increased the bioavailability of tramadol and O-desmethyltramadol in a dose-dependent manner, highlighting their potential interactions and emphasizing the need for further dose optimization in donkey analgesic therapies. In conclusion, metamizole co-administered with tramadol interferes with metabolism and this interference can change the frequency of drug administration and its analgesic efficacy.

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus).

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3 hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663 ± 1,827 vs. T4: 2,964 ± 1,038 ng*h/ml) and M1 (T2: 378 ± 237 vs. T4: 345 ± 142 ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2 mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys.

[Prevalence and genotypic characterization of methicillin-resistant strains of Staphylococcus aureus isolated in a Mexican regional hospital]. / Prevalencia y caracterización genotípica de cepas de Staphylococcus aureus resistente a meticilina aisladas en un hospital regional mexicano.

BACKGROUND: Staphylococcus aureus is one of most prevalent pathogens in the world associated with a high mortality rate and a rapid development of resistance to antibiotics. Despite its pathogenicity, epidemiological monitoring in Mexico is scarce. AIM: To analyze the local molecular epidemiology and determine the clonal origin of methicillin-resistant (MR) strains isolated from patients admitted to Hospital "Dr. Ignacio Morones Prieto". METHODS: A cross-sectional prospective study was carried out from July to December 2016. The characterization of the strains was carried out by Spa genotyping, frequency of specific virulence genes by PCR and antibiogram. RESULTS: The prevalence of MRSA was 25.7%, highlighting the presence of the Spa type t895 in 76% of the resistant strains and a similar pattern of susceptibility to antibiotics. CONCLUSION: The results of this study indicate that the regional prevalence of MRSA has not changed in the last 10 years and provide valuable information on the clonal origin and the virulence factors of the strains of S. aureus isolated in the region.

Oral Ciprofloxacin Pharmacokinetics in Healthy Mexican Volunteers and Other Populations: Is There Interethnic Variability?

BACKGROUND: There is evidence that the pharmacokinetics of certain drugs in Mexicans may differ with respect to other ethnic groups. On the other hand, there is controversy about the existence of interethnic variability in the pharmacokinetics of ciprofloxacin. AIM OF THE STUDY: To study oral ciprofloxacin pharmacokinetics in Mexicans at various dose levels and make comparisons with other populations in order to gain insight on interethnic variability. METHODS: Healthy Mexican volunteers received oral ciprofloxacin as 250 mg and 500 mg immediate-release tablets or a 1,000 mg extended-release formulation. Plasma concentration against time curves were constructed, and pharmacokinetic parameters were compared with those reported for other populations. RESULTS: Ciprofloxacin pharmacokinetics in Mexicans was linear and no significant differences between males and females were detected. When several populations were compared, it appeared that bioavailability in Mexicans was similar to that of Caucasians, being lower than that of Asians. These variations were attenuated when data were normalized by body weight. CONCLUSIONS: Ciprofloxacin pharmacokinetics exhibit interethnic variability, Asians exhibiting an increased bioavailability with regard to Mexicans and Caucasians. Data suggest that these differences are due to body weight.

Prevalencia y caracterización genotípica de cepas de Staphylococcus aureus resistente a meticilina aisladas en un hospital regional mexicano / Prevalence and genotypic characterization of methicillin-resistant strains of Staphylococcus aureus isolated in a Mexican regional hospital

Resumen Introducción: Staphylococcus aureus es uno de los patógenos con mayor prevalencia en el mundo, asociado a una alta tasa de mortalidad y un rápido desarrollo de resistencia a los antimicrobianos. A pesar de su patogenicidad, su seguimiento epidemiológico en México es escaso. Objetivo: Analizar la epidemiología molecular local y determinar el origen clonal de cepas resistentes a meticilina (RM) aisladas de pacientes internados en el Hospital Central "Dr. Ignacio Morones Prieto". Métodos: Se llevó a cabo un estudio prospectivo de corte transversal, de julio a diciembre de 2016. La caracterización de las cepas se realizó mediante genotipificación Spa, la determinación por RPC punto final de la frecuencia de genes de virulencia específicos y su antibiograma. Resultados: A partir de estos datos, se obtuvo que la prevalencia de S. aureus RM fue de 25,7%, destacando la presencia del tipo Spa t895 en 76% de las cepas resistentes y un patrón similar de susceptibilidad a antimicrobianos. Conclusión: Los resultados de este estudio indican que la prevalencia regional de SARM no se ha modificado en los últimos 10 años y proporcionan información valiosa del origen clonal y los factores de virulencia de las cepas de S. aureus aisladas en la región.

Abstract Background: Staphylococcus aureus is one of most prevalent pathogens in the world associated with a high mortality rate and a rapid development of resistance to antibiotics. Despite its pathogenicity, epidemiological monitoring in Mexico is scarce. Aim: To analyze the local molecular epidemiology and determine the clonal origin of methicillin-resistant (MR) strains isolated from patients admitted to Hospital "Dr. Ignacio Morones Prieto". Methods: A cross-sectional prospective study was carried out from July to December 2016. The characterization of the strains was carried out by Spa genotyping, frequency of specific virulence genes by PCR and antibiogram. Results: The prevalence of MRSA was 25.7%, highlighting the presence of the Spa type t895 in 76% of the resistant strains and a similar pattern of susceptibility to antibiotics. Conclusion: The results of this study indicate that the regional prevalence of MRSA has not changed in the last 10 years and provide valuable information on the clonal origin and the virulence factors of the strains of S. aureus isolated in the region.

Thermo-reversible in situ forming implant with nanostructured lipid carriers (NLC) as a delivery system for the administration of estradiol valerate.

A thermo-reversible in situ forming implant, based on the combination of Pluronic® F-127 and Pluronic® F-68 with nanostructured lipid carriers (NLC), was formulated with the aim of achieving the sustained release of estradiol valerate (EV). EV-loaded NLC, prepared by the hot high-pressure homogenization technique, presented an entrapment efficiency of 90 ± 2.9 %, a particle size (PS) of 122 ± 11.2 nm, a polydispersity index (PDI) of 0.344 ± 0.07, and a zeta potential (ZP) of - 10.5 ± 1.3 mV. Once obtained, NLC were then included in a thermo-reversible gel (EV-loaded NLC gel), which was characterized by its rheological behavior, gelation temperature, and injectability. The in vitro release tests showed that the EV-loaded NLC gel delayed the release significantly, in comparison with a solution of the drug and with the EV-loaded NLC. The EV-loaded NLC gel and a commercially available suspension containing estradiol were administered parenterally to rabbits. A 16.8-fold greater AUC and a 40-fold higher Cmax were obtained with the EV-loaded NLC gel, compared to the commercial suspension. A rapid initial release of EV in vivo, from the EV-loaded NLC gel, suggests that it is necessary to adjust the ratio of the copolymers or to include in the gel an additive that improves gelation time and gel strength, in order to achieve a sustained release. An interesting observation was that the in vitro profile, which has a three-phase behavior, coincides with what was observed in the in vivo study. Graphical abstract.

Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo-controlled clinical trial

BACKGROUND: Preemptive analgesia is considered an alternative for treating the postsurgical pain of third molar removal. The aim of this study was to evaluate the preemptive analgesic efficacy of oral ketorolac versus intramuscular tramadol after a mandibular third molar surgery. MATERIAL AND METHODS: A parallel, double-blind, randomized, placebo-controlled clinical trial was carried out. Thirty patients were randomized into two treatment groups using a series of random numbers: Group A, oral ketorolac 10 mg plus intramuscular placebo (1 mL saline solution); or Group B, oral placebo (similar tablet to oral ketorolac) plus intramuscular tramadol 50 mg diluted in 1 mL saline solution. These treatments were given 30 min before the surgery. We evaluated the time of first analgesic rescue medication, pain intensity, total analgesic consumption and adverse effects. RESULTS: Patients taking oral ketorolac had longer time of analgesic covering and less postoperative pain when compared with patients receiving intramuscular tramadol. CONCLUSIONS: According to the VAS and AUC results, this study suggests that 10 mg of oral ketorolac had superior analgesic effect than 50 mg of tramadol when administered before a mandibular third molar surgery

Antinociceptive Activity of an Ethanol Extract of Justicia spicigera.

Preclinical Research The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine-induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180-186, 2016. © 2016 Wiley Periodicals, Inc.

Parecoxib Increases Blood Pressure Through Inhibition of Cyclooxygenase-2 Messenger RNA in an Experimental Model.

BACKGROUND: Cyclooxygenase-2 selective inhibitors have been developed to alleviate pain and inflammation; however, the use of a selective cyclooxygenase-2 inhibitor is associated with mild edema, hypertension, and cardiovascular risk. AIM: To evaluate, in an experimental model in normotensive rats, the effect of treatment with parecoxib in comparison with diclofenac and aspirin and L-NAME, a non-selective nitric oxide synthetase, on mean arterial blood pressure, and cyclooxygenase-1 and -2 messenger RNA and protein expression in aortic tissue. METHODS: Rats were treated for seven days with parecoxib (10 mg/kg/day), diclofenac (3.2 mg/kg/day), aspirin (10 mg/kg/day), or L-NAME (10 mg/kg/day). Mean arterial blood pressure was evaluated in rat tail; cyclooxygenase-1 and -2 were evaluated by reverse transcription-polymerase chain reaction and Western blot analysis in aortic tissue. RESULTS: Parecoxib and L-NAME, but not aspirin and diclofenac, increased mean arterial blood pressure by about 50% (p < 0.05) without changes in cardiac frequency. Messenger RNA cyclooxygenase-1 expression in aortic tissue was not modified with any drug (p < 0.05). L-NAME and parecoxib treatment decreased messenger RNA cyclooxygenase-2 and cyclooxygenase-2 (p < 0.05). While cyclooxygenase-1 protein decreased with the three drugs tested but not with L-NAME (p < 0.05), the cyclooxygenase-2 protein decreased only with aspirin and parecoxib (p < 0.05). CONCLUSION: Parecoxib increases the blood pressure of normotensive rats by the suppression of COX-2 gene expression, which apparently induced cardiovascular control.

Risk factors and biofilm detection on central venous catheters of patients attended at tertiary hospital.

AIM: To determinate the significance of risk factors with the presence of biofilm on catheters of patients attended at tertiary hospital cares. MATERIAL AND METHODS: A total of 126 patients were included, data collection by observing the handling of the CVC, clinical history and microbiological isolation methods of CVCs tips (Roll-plate, sonication and scanning electron microscopy) were evaluated. RESULTS: Certain factors, such as the lack of proper hand washing, the use of primary barriers and preparing medications in the same hospital service, showed an important relationship between biofilm formation in CVCs. The sonication method presented that most of the samples had isolation of multispecies 29 samples (64%); in contrast with the roll-plate method, just one sample (3%) was isolated. CONCLUSIONS: The importance of the strict aseptic techniques of insertion and of the handlings of CVC was highlighted, the failure of both techniques was related to the biofilm formation and was evidenced using the scanning electron microscopy. Since this tool is not available in most hospitals, we present the correlation of those evidences with other standard microbiological methods and risk factors, which are necessary for the sensible detection of the different steps of the biofilm formation on CVC and their correct interpretation with clinical evidences.

[Preclinical in vitro and in vivo models for the assessment of biological activity in biosimilarity studies]. / Modelos preclínicos in vitro e in vivo para la evaluación de la actividad biológica en estudios de biocomparabilidad.

A drug that contains a recombinant protein as an active principle is called a biotechnological drug or biopharmaceutical.There are currently over 300 biopharmaceuticals worldwide. Many of these contains a similar active principle (biosimilar drug) as other previously registered (innovator drug). It has suggested that due to the complex implications in a formulation containing a protein, the manufacturing process is a key factor for efficacy and safety requirements. In fact, certain variability has been detected of the protein properties in different lots (or batches) of the same manufacturer, which produce changes at a clinical level. For this reason, the evaluation of biosimilar drugs has acquired great relevance, being the preclinical level of one of the more important stages of the development due to its lower cost (with respect to the clinical level) and its high capacity to detect formulation-manufacture problems. However, the demonstration of comparability at physicochemical, preclinical, and clinical levels is required in order to achieve market registration. In this review the in vitro and in vivo models used for the assessment of proposed biosimilars will be discussed.

Determination of Pinaverium Bromide in Human Plasma by a Sensitive and Robust UPLC-MS-MS Method and Application to a Pharmacokinetic Study in Mexican Subjects.

A high-throughput ultra-performance liquid chromatography coupled to tandem mass spectrometry (LC-ESI-MS-MS) method was developed for the determination of pinaverium bromide in human plasma. Protein precipitation with acetonitrile was used to extract pinaverium and itraconazole (as internal standard) from 500 µL plasma samples. The chromatographic separation was achieved with an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) using a mixture of acetonitrile-5 mM ammonium formate (80:20, v/v) as mobile phase. Isocratic elution at 0.3 mL/min was used. Detection was performed by positive ion electrospray tandem mass spectrometry on a XEVO TQ-S by multiple reaction monitoring mode. The mass transitions monitorized were as follows: m/z 511.2 → 230 for pinaverium bromide, and m/z 705.29 → 392.18 for the itraconazole. The method was validated over a concentration range of 12-12,000 pg/mL. The chromatographic method runtime is 2.5 min and was applied to characterize the pharmacokinetics of pinaverium bromide after the oral administration of 100 mg to healthy Mexican subjects.

Absence of a significant pharmacokinetic interaction between atorvastatin and fenofibrate: a randomized, crossover, study of a fixed-dose formulation in healthy Mexican subjects.

Several clinical trials have substantiated the efficacy of the co-administration of statins like atorvastatin (ATO) and fibrates. Without information currently available about the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the effect when both drugs were co-administered. The purpose of this study was to investigate the pharmacokinetic profile of tablets containing ATO 20 mg, or the combination of ATO 20 mg with fenofibrate (FNO) 160 mg administered to healthy Mexican volunteers. This was a randomized, two-period, two-sequence, crossover study; 36 eligible subjects aged between 20-50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for ATO as the reference and ATO and FNO as the test product for bioequivalence design. The estimation computed (90% confidence intervals) for ATO and FNO combination versus ATO for Cmax, AUC0-t and AUC0-∞, were 102,09, 125,95, and 120,97%, respectively. These results suggest that ATO and FNO have no relevant clinical-pharmacokinetic drug interaction.

Pharmacokinetic non-interaction analysis in a fixed-dose formulation in combination of atorvastatin and ezetimibe.

Recent clinical research has shown that atorvastatin (ATO) in combination with cholesterol absorption inhibitor ezetimibe (EZE) significantly reduces LDL-C level in patients with hypercholesterolemia, showing a superior lipid-lowering efficacy compared to statin alone. With no information currently available on the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the influence of EZE on ATO and conversely when the two drugs were coadministered. The purpose of this study was to investigate the presence of differences in the pharmacokinetic profiles of capsules containing ATO 80 mg, EZE 10 mg or the combination of both 80/10 mg administered to healthy Mexican volunteers. This was a randomized, three-period, six-sequences crossover study. 36 eligible subjects aged between 20 to 50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for each drug alone or together and tested for bioequivalence-based hypothesis. The estimation computed (90% confidence intervals) for AUC and Cmax, were 96.04% (85.88-107.42%) and 97.04% (82.36-114.35%), respectively for ATO-EZE combination versus ATO alone, while 84.42% (77.19-92.32%) and 95.60% (82.43-110.88%), respectively, for ATO-EZE combination versus EZE alone were estimated. These results suggest that ATO and EZE have no relevant pharmacokinetic drug-drug interaction.

Involvement of nitric oxide and ATP-sensitive potassium channels in the peripheral antinoceptive action of a tramadol-dexketoprofen combination in the formalin test.

Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate pathway and ATP-sensitive K(+) channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin-injured mouse paw and the antinociceptive effect evaluated. ED50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l-NG-nitroarginine methyl ester and 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, or the ATP-sensitive K(+) channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol-dexketoprofen combination, suggesting that NO and ATP-sensitive K(+) channels were involved.

Peripheral synergism between tramadol and ibuprofen in the formalin test.

Preclinical Research Analgesics with different mechanisms of action can be combined in order to obtain pharmacological synergism, employing lower doses of each agent, thus diminishing side effects. For instance, an atypical dual analgesic such as tramadol (TMD) and a nonsteroidal anti-inflammatory drug such as ibuprofen (IBU) are good candidates to be evaluated when combined and applied peripherally. The present study was conducted to evaluate possible local synergism between TMD and IBU when combined peripherally using the formalin test in rats. The effects of the individual analgesics and their combinations were evaluated simultaneously using a 5% formalin dilution. Dose-effect curves were determined for TMD (50-400 µg/paw) and IBU (1-100 µg/paw). Experimental effective doses were evaluated and isobolographic analyses were constructed to evaluate TMD-IBU combination synergism. Both drugs produced a dose-dependent analgesic effect when applied separately. Isobolographic analysis showed synergism during phase 1 (0-10 min) and phase 2 (15-60 min) when compared with theoretical doses (P < 0.05), with interaction indexes of 0.06 and 0.09, respectively. The present information supports the peripheral analgesic effect of TMD and IBU, especially when combined at appropriate doses.

Design of a controlled release system of OP-1 and TGF-ß1 based in microparticles of sodium alginate and release characterization by HPLC-UV.

A new system for sustained release of growth factors, such as osteogenic protein 1 (OP-1) and transforming growth factor ß1 (TGF-ß1), intended to repair and promote dental tissue regeneration in rats was designed and characterized in this work. The release system was made with microparticles of sodium alginate, produced by ionic gelling dripping technique. The release profiles of OP-1 and TGF-ß1 from biopolymer matrix were determined by high-performance liquid chromatography (HPLC), and with this purpose, an HPLC-UV method was developed. About 80% of each growth factor was released in the first 24 h, reaching almost 100% in 168 h. The system was tested during the tissue repair in rat molars in comparison with calcium hydroxide and both growth factors not encapsulated. The dentin sialoprotein (DSP) was used as a repair marker. It was detected by immunohistochemistry, after 14- and 28-d post-treatment. X (2) test (p ≤ 0.001) and Fisher exact test (p ≤ 0.05) were applied for assessment of the amount of immunostaining. The treatment with encapsulated OP-1 showed an increased DSP immunostaining after 14 d and did not find any significant difference with the immunostaining observed for calcium hydroxide treatment. Treatment with TGF-ß1 did not show significant difference with calcium hydroxide. Treatment with both factors OP-1 and TGF-ß1 showed higher DSP immunostaining in comparison with calcium hydroxide treatment. In conclusion, the combination of both growth factors encapsulated showed more DSP immunostaining in comparison with each one separated, either encapsulated or not.

Preemptive analgesic effectiveness of oral ketorolac plus local tramadol afterimpacted mandibular third molar surgery

Objective: The aim of this study was to compare preemptive analgesia of oral ketorolac plus submucous localplacebo with oral ketorolac plus submucous local tramadol after impacted mandibular third molar surgery.Study design: A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were randomizedinto two treatment groups (n = 15 per group): group A, oral ketorolac 10 mg, 30 minutes before surgeryplus submucous local placebo (1 mL saline solution); group B, oral ketorolac 10 mg, 30 minutes before surgeryplus submucous local tramadol (50 mg diluted in 1 mL saline solution). We evaluated the intensity of pain, timefor the first analgesic rescue medication, and total analgesic consumption.Results: Pain intensity, number of patients requiring analgesic rescue medication, number of patients in each groupnot requiring analgesic rescue medication, and total analgesic consumption showed statistical significance.Conclusions: Preemptive use of oral ketorolac plus submucous local tramadol is an alternative treatment for acutepain after surgical removal of an impacted mandibular third molar (AU)

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Preemptive analgesic effectiveness of oral ketorolac plus local tramadol after impacted mandibular third molar surgery.

OBJECTIVE: The aim of this study was to compare preemptive analgesia of oral ketorolac plus submucous local placebo with oral ketorolac plus submucous local tramadol after impacted mandibular third molar surgery. STUDY DESIGN: A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were randomized into two treatment groups (n = 15 per group): group A, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local placebo (1 mL saline solution); group B, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local tramadol (50 mg diluted in 1 mL saline solution). We evaluated the intensity of pain, time for the first analgesic rescue medication, and total analgesic consumption. RESULTS: Pain intensity, number of patients requiring analgesic rescue medication, number of patients in each group not requiring analgesic rescue medication, and total analgesic consumption showed statistical significance. CONCLUSIONS: Preemptive use of oral ketorolac plus submucous local tramadol is an alternative treatment for acute pain after surgical removal of an impacted mandibular third molar.