Study of the analgesic efficacy of Dexketoprofen Trometamol
25mg. vs. Ibuprofen 600mg. after their administration in patients subjected to oral surgery

JIMÉNEZ-MARTÍNEZ E, GASCO-GARCÍA C, ARRIETA-BLANCO JJ, GÓMEZ DEL TORNO J, BARTOLOME-VILLAR B. STUDY OF THE ANALGESIC EFFICACY OF DEXKETOPROFEN TROMETAMOL 25 MG. VS IBUPROFEN 600MG. AFTER THEIR ADMINISTRATION IN PATIENTS SUBJECTED TOORAL SURGERY. MED ORAL 2004;9:138-48.

SUMMARY

-Objectives: Compare the analgesic efficacy of two non-steroidal anti-inflammatory drugs (NSAIDs) belonging to the family of propionic acids after oral surgery in order to assess which one is most effective with the minimum side effects and lowest dose. Normally, the pain after oral surgery is considered as moderate-intense and NSAIDs are the first choice when treating post-surgical dental pain. As we know, the great problem of these drugs is found in their undesirable effects. The enantiomer-S(+) component is known to be related with analgesia and need for lower dose of these drugs.
-Design: The patients are given questionnaires with pain assessment tables and different observations are made: post-surgical pain, pain in the first hour after administration of the analgesic, inflammation, bleeding, hematoma, etc. We assess the effect of the different drugs used in the study based on the efficacy-time coordinates as well as the anti-inflammatory effect and their side effects.
-Results: It is verified that there is moderate pain after oral surgery and the drugs used are effective in the doses and intervals indicated. During the first hour after taking the analgesic, those patients treated with Dexketoprofen Trometamol (DKT) presented less pain compared to those who were treated with Ibuprofen (IBU). It is verified that there is inflammation in most of the interventions, the extractions of the semi-impacted third molars (SITM) present greater bleeding on the first day and the extractions of impacted third molars (ITM) present more bleeding on the third day. These last two interventions (ITM also present hematoma.
-Conclusions: We demonstrate the greater analgesic efficacy of Dexketoprofen Trometamol in the first hour after the oral surgical intervention and its greater anti-inflammatory effect.

Key words: Oral surgery, Dexketoprofen Trometamol, Ibuprofen.

INTRODUCTION

In the decade of the seventies, Winter (1) and Cooper and Beaver (2,3) developed a standard model to assess pain and efficacy of analgesics on the extraction of the lower third molar. Since then, many therapeutic studies have been performed with different drugs, especially with non-steroidal anti-inflammatory drugs (NSAIDs) (4-11). In these cases, the pain generally has a moderate to serious intensity and need for treatment generally occurs during the first 24-48 hours after the intervention (12,13).

Post-surgical pain occurs as a response to the tissular injury and the reparative phenomena that the body initiates; it is related with the inflammatory conditions that cause pain, edema, increased local temperature, etc. (14). The pain reaches moderate to serious intensity at 5 hours, on the contrary, edema reaches its peak between 48 and 72 hours after extracting the impacted third molars (14,15). The maximum concentration of prostaglandins in an acute tissular aggression appears simultaneously with the post-operative pain intensity peak. IBU is the best known NSAIDs used in dental practice (15-25).

The ideal analgesic (26,27) should fulfill the following conditions: elevated analgesic potency, fast action, long lasting analgesic effect, without risk of addiction and tolerability, low risk of adverse reactions and comfortable to administer. Up to now, the NSAIDs have been the drugs of choice in the treatment of dental pain; their analgesic and anti-inflammatory properties are attributed to the inhibition of the cyclooxygenase pathway (COX-1 and COX-2).

Since some years ago, NSAIDs that are selective of COX-2 (28), an enzyme that is expressed in cells affected or related with tissular trauma, are being developed, thus achieving decrease in most of the undesirable effects of these drugs, above all the gastrointestinal ones (8,10,29,30). It has been verified that hemorrhagic gastropathy caused by NSAIDs is associated with the inhibition of the prostaglandin synthesis in the stomach and intestinal walls (29,31). This adverse effect is related with the active enantiomer S (+), which is the one that inhibits the cyclooxygenase.

There are certain differences in the action spectrum of the different NSAIDs (27,32): as their acid character, which makes them bind to plasma proteins and they are attracted by inflamed tissues, and their degree of binding to the plasma proteins, that can interfere in the binding of these to warfarin. However, in studies performed in vitro, it has not been demonstrated that doses of 2,400 mg/day interfere with the binding of warfarin to the plasma proteins, which could alter the coagulation (33). On the other hand, some have more anti-inflammatory and analgesic properties (from greater to lesser pharmacological potency in vitro: Flurbiprofen, Ketoprofen, Fenoprofen, Naproxen and Ibuprofen) and the greater difference is generally found in the side effects they produce (13,15).

We describe the two NSAIDs that motivate this study in more detail:

Dexketoprofen Trometamol (DKT) (34-37) is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen. Racemic ketoprofen has been used since 1973 as an analgesic, anti-pyretic and anti-inflammatory agent and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the S(+)-enantiomer dexketoprofen, while the R(-) enantiomer lacks such activity. The ulcerogenic action of the trometamol salts, especially dexketoprofen trometamol, is very low; specifically, the number of lesions caused by this compound is 5 times lower than that due to racemic acid (35,38). In the human being, the relative bioavailability of oral DKT in 25 mg dose is similar to that of oral racemic ketoprofen in 50 mg dose. DKT administered orally reaches maximum plasma concentration between 0.25-0.75 hours while for the racemic drug takes 0.5-3 hours. It has been proven that the plasma concentration of DKT is 3.1 mg/l (36), while that of racemic ketoprofen has not been determined.

Ibuprofen was synthesized in England in the early sixties and introduced into America in 1974. In the beginning, it was used as an antiarthritic agent and in the decade of the eighties, it was indicated for the treatment of dysmenorrhea, inflammation and fever. It belongs to the family of propionic acids. In regards to their pharmacokinetic characteristics, they are well absorbed orally, although the presence of food reduces the absorption rate but not the total amount absorbed (39).

As any NSAID, its action mechanism is based mainly on the inhibition of the cyclooxygenase activity and the greatest disadvantages of these drugs are the upper gastrointestinal tract disorders (40).

OBJECTIVES

In the development of this study, we have used two NSAIDs belonging to the Propionic Acid family (Ibuprofen and Dexketoprofen Trometamol). We assess the analgesic potency of Dexketoprofen Trometamol (7,9,15,26,32-38) from the clinical point of view and compare it with that of Ibuprofen.

We will assess a deep and acute somatic pain, equivalent to the post-surgical dental pain, that responds to analgesics. The main objective of the study will be to evaluate analgesic efficacy after the administration of 25 mg. of Dexketoprofen Trometamol compared with 600 mg. of Ibuprofen in patients undergoing oral surgical interventions consisting in extractions of impacted (ITM) and semi-impacted (SITM) third molars that present acute pain after dental treatment.

We will assess the effectivity of the drugs, based on the efficacy-time coordinates, the efficacy in time after repeated doses, and the existence of side effects and the post-operative complications (inflammation, bleeding, hematoma and/or infection).

MATERIAL AND METHODS

A comparative study was performed on two analgesics (Ibuprofen and Dexketoprofen Trometamol) in the Stomatology Service of the Jiménez Díaz Foundation on 93 patients belonging to the National Health System, whose ages ranged from 18 to 65 years and who underwent oral surgery consisting in extraction of the impacted or semi-impacted third molars in the period ranging from September 2000 to May 2001.

The exclusion criteria for the extractions performed were: extraction of either partially impacted (submucosa or partial intraosseous) or totally impacted unilateral third molars.

The exclusion criteria were: patients in treatment 24 hours before the surgery with some analgesic and/or anti-pyretic agent; those patients who took some other drug during the study besides that in the guideline that could alter the bioavailability of the study drug were not included; patients allergic to any of the drugs used were also not included in the study; patients with poorly controlled associated disease such as: heart disease, coagulation disorders, thyroid disorders, etc. All the patients gave their informed consent before the operation to be included in the study; it was performed in agreement with the Declaration of Helsinki principles and with the previous authorization of the Institutional Review Board.

First, a presurgical visit was performed in which a complete medical history and dental examination as well as a panoramic X-ray were carried out to assess the type of extraction to be performed and to make the pre-operative guidelines. All the patients (except those who presented some type of intolerability or allergy, who were not included in the study) were routinely administered antimicrobial therapy, following the Service protocol, consisting in: amoxicillin 500 mg, every 8 hours, for 5 days, beginning the day before surgery.

The surgical interventions were performed in the Hospital dental clinic and the extractions were performed by two dentists (always the same) from the last post-graduate course of the Oral Surgery program of the Jimenez Diaz Foundation (FJD). In all the surgical interventions, mucoperiosteal flap and osteotomy were performed. The suture used was braided silk 2-0. The anesthesia used was 2% lidocaine HC1 and epinephrine 1:100,000, except if the patient presented any well controlled cardiovascular disease (as background of myocardial infarction, arrythmias, coagulation disorders, etc.), in which case 3% mepivacaine was used. In no case was sedation used to perform the surgery. The drugs compared in this study are:

- Dexketoprofen trometamol 25mg.;

- Ibuprofen 600mg.

The drugs were distributed randomly and no placebo group was used. Furthermore, to assess the pain intensity, the pain degree presented by the patient after the surgery and before taking the analgesic was used as a reference. The dose given is one tablet every 8 hours for 3 days, and the patient began to take the drug at two hours of the onset of surgery, except for if the patient had pain earlier. Of the cases studied, 57 patients began to take the analgesic at two hours of the surgery, 10 patients began to take the analgesic before two hours and the rest (26 patients) took longer than two hours to begin to take the analgesic. No rescue drug was given.

In the questionnaire given to the patient at the end of the treatment, the dentists collected the personal data, type of surgery performed, type of analgesic administered, administration regime and pain assessment tables.

The patients filled out the tables in which the pain intensity scales were specified and the questionnaire was given to them the following week when they came to have their stitches removed. If the patient lived outside of the Regional Community of Madrid, a stamped envelope was provided so that the questionnaire could be mailed to us. Considering that the parameters to be assessed are totally subjective, tables with assessment scales on the pain intensity were made in order to unify the evaluations of each patient (see table 1).

These pain assessment scales were:

- Visual analogue scale (VAS), on a horizontal line of 0 (absence of pain) to 100 mm (the greatest pain imaginable), the patient indicates the intensity of the post-operative pain at 2 hours of the surgery and before taking the analgesic.

- Verbal analogue scale to assess pain intensity after the surgery and before taking the analgesic.

- Verbal analogue scale to assess pain intensity after the administration of the analgesic. Measured in the first, sixth and eight hour after its administration.

- Assessment scale on the signs of the patient the days following the surgery; if there is bleeding, inflammation, hematoma or abscess, specifying if this occurs on the first, second or third day (see table 1).

If an analgesic had to be taken during the first day before the eight hours established in the guideline had passed, the patient indicated this as well as the existence of possible side effects due to the drug on the questionnaire.

Of the variables analyzed in this study, we have used those that were significant in our dental pain model (pain intensity in the first hour after taking the analgesic, presence of bleeding and appearance of hematoma). Post-surgical pain was evaluated at two hours of the intervention. These data were assessed based on the type of extraction and type of analgesic administered.

The study of the variables is made with contingency tables. The Pearson's Chi-squared test is applied to observe if there are significant differences between the percentages. The statistical analysis was done with the BMDP statistical software (1992, University of California Press. Dixon W.J.), the significance level being: p<0.05.

RESULTS

Of the 93 patients between 18 and 65 years of age, 59 women and 34 men, the mean age was 26.46 years. Of these patients, 49.46% (46 patients) were treated with Ibuprofen 600 mg and 50.53% (47 patients) with Dexketoprofen Trometamol 25 mg. The surgery procedure lasted 30 to 45 minutes, depending on the type of extraction.

Of the interventions performed (93 cases), 47 cases corresponded to surgical extractions of impacted third molars (ITM=50.53%) and 46 cases corresponded to semi-impacted third molar extractions (SITM=49.46%).

In general, after the surgical procedure (at 2 hours of the surgery), the pain was mainly classified as mild (39.8%) and moderate (30.1%).

In the 1st hour after taking the analgesic, a major percentage of the patients subjected to impacted (ITM) and semi-impacted third molar (SITM) extractions who were receiving treatment with DKT did not present pain (25.5%, 12 cases) or presented mild pain (44.7%, 21 cases) compared to those who were receiving treatment with IBU, of whom 6.5% (3 cases) did not present pain or 32.6% (15 cases) presented mild pain (table 1, p = 0.0070). In regards to pain intensity at the 6th and 8th hour after taking the analgesic, no significant differences were observed in relationship with the type of extraction and analgesic administered: in the 6th hour after taking the analgesic, 15.2% (7 cases) of the patients treated with IBU did not present pain compared to 12.8% (6 cases) of the patients who were receiving treatment with DKT. Mild pain was presented by 28.3% (13 cases) of the patient who were receiving treatment with IBU and 21.3% (10 cases) of the patients treated with DKT and intense pain was presented by 17.4% (8 cases) of the patients treated with IBU and 27.7% (13 cases) of those treated with DKT (table 2, p=0.6485). In regards to the need to take analgesics before the 8 hours established in the guideline, there were also no significant differences between the type of surgery performed and the analgesic administered.

A total of 34.4% of the patients (32 cases) did not present bleeding and there was a greater incidence of bleeding during the first day after the intervention (49.5%, 46 cases), extraction of the semi-impacted third molar was the intervention that caused the greatest incidence of bleeding (65.2%, 30 cases) (table 3, p=0.0086). No significant differences were obtained in regards to the presence of bleeding in relationship with the type of intervention and analgesic administered.

The appearance of hematoma was observed on the third day in ITM in 19.1% (9 cases) and in SITM in 6.5% (3 cases), there being no relationship with the analgesic administered; 87.1% (81 cases) did not present hematoma.

In regards to inflammation, we observed that 9.7% of the patients did not present inflammation, however during the second and third day, 80.6% of the patients presented inflammation, regardless of the type of intervention performed, although these values were not statistically significant.

DISCUSSION

Post-operative acute pain related to surgical dental treatment can be divided into three large groups (3,4): complicated oral surgery, periodontal surgery and impacted third molar extraction surgery. On the other hand, the type of patient chosen is relatively young (26.46 years) with the capacity to understand and fill out the questionnaire, in which, as we have previously analyzed, the patient indicates the pain intensity degree on different scales (visual and verbal analogue). In this study, the visual scale was not statistically assessed because the patients did not fill it out correctly, since the scoring of 0 (no pain) to 100 (the greatest pain) in intervals of ten to ten did not correspond with the numbers on the numeric scale. Thus, a pain scored as moderate by the patient on the numeric scale (3-4) did not correspond with a pain assessment by the patient of 10/100 on the visual scale.

The patients come to the Hospital through the National Health System (Social Security).

In our study, the indications for the surgeries were mainly acute pain pictures, presence of apical focus associated to the tooth to be extracted and/or cystic pathology associated to impacted third molars. Generally, there is greater pain after surgical extraction of the lower third molar due to its anatomic position. The pericoronaritis and lack of space are the most frequent causes that make extraction of the lower third molar necessary (24).

In the treatment of acute pain, the NSAID analgesics (as the derivatives of propionic acids) are mainly used since they are those indicated in this type of pain due to their pharmacocokinetic properties. In studies performed in vivo, the effectivity of the NSAIDs derived from the chiral aryl-propionic acids (as Ketoprofen) has been verified. Specifically it has been possible to verify that the administration of the enantiomer S(+)-Ketoprofen has many benefits compared with the racemic component and it presents a more favorable tolerability profile (7), a decrease of pharmacokinetics variability, less accumulation of the drug in the lipids and decrease of risk of pharmacodynamic and pharmacokinetic interactions with concomitant drugs. Similar results are obtained after administering doses of Ibuprofen 400 mg and Dexketoprofen Trometamol 20 mg after oral surgical interventions, Dexketoprofen Trometamol being the one that produces the greatest pain relief after its administration, however, duration of the analgesia was shorter than in the cases in which Ibuprofen 400 mg. was administered (C.Gay et al. 1996) (7). In any event, few comparative studies exist on Ibuprofen and Dexketoprofen, five being counted from the year 1996 to the present.

We compare the drugs Ibuprofen and Dexketoprofen Trometamol at different doses since the Ibuprofen dose for moderate dental pain is 600 mg according to the International Guideline and the Dexketoprofen Trometamol dose is 25 mg. (9).

No placebo group was used since we consider that the type of interventions we perform are those occurring with the greatest pain within the general pain classifications, and considering that one of the study drugs (Ibuprofen) is the only one used for this type of pain in the Stomatology Service and that it is included in the protocols for the treatment of the pain of the symptoms, it can be considered that the patients receiving this drug can be used as a control group.

The questionnaire given to the patients includes pain assessment tables similar to those used in other studies (5,7,9). Of the results obtained in our study, we have used those variables which, being significant, allow us to make conclusions and accurately assess the effectivity of the drugs studied.

We could verify that after the surgical intervention, the type of pain presented by the patients was mild (39.8%) and moderate (30.1%).

In other studies, after oral surgical interventions, post-operative pain had a 3.1 value in a numeric scale (scoring of 0 to 4) that is equivalent to moderate pain (9).

We have verified that in the 1st hour after taking the analgesic after ITM and SITM interventions, DKT is more effective. In this measurement, the effect of the anesthesia has normally disappeared, since in most of the 93 cases, it took two hours or more for the patient to begin to take the analgesic after the surgery (83 patients began to take the analgesic more than two hours after the surgery) in addition to the surgery time (30 to 45 minutes). This coincides with the results obtained by other authors, who have clinically compared Dexketoprofen Trometamol 12.5 or 25 mg and Dipyrone 575 mg in dental pain (5). Pain intensity and its relief were assessed at regular intervals. In global efficacy, it was seen that Dexketoprofen Trometamol in either of the two doses administered was more effective than Dipyrone (5). In the sixth hour after taking the drug, the patients who had undergone extraction of an impacted third molar generally presented moderate pain, there being no significant differences in regards to the analgesic administered. Generally, administration of an additional analgesic was not necessary before eight hours had passed from the previous dose, except in a few cases of impacted third molar extractions (22 cases) which are the procedures that have a greater traumatism of the tissues, in which case, the need for an analgesic was every six hours during the first day. All of the interventions carried out are surgical extractions of ITM and SITM performed by two dentists (post-graduates of the last Master's course of Oral Surgery of the FJD), among which the author is included, using the same surgical technique for the extraction of the third molars (mucoperiostic flap and osteotomy). This made it possible to see which analgesic is the most effective during the first eight hours. This result coincides with that of other studies such as that of Bagan et al. (5), in which the analgesic administration regime after the surgical intervention of impacted third molars, both with Dipyrone 575 mg as well as DKT 25 mg, was approximately 1 dose every 5 hours and 30 minutes (5,9,11,37).

No studies have been found on the complications after the surgery and treatment with these drugs. As the patients were not being treated with any other analgesic, we did not see any interactions related to other drugs or complications related with the presence of bleeding, inflammation or hematoma in the two or three days after the surgery (41).

Normally, the degree of inflammation after the extraction is related with the surgical difficulty, intervention time and patient's defense level.

The differences observed between DKT and Ibuprofen in regards to the analgesic and anti-inflammatory effect were not significant since the p<0.05 value was not fulfilled in the statistical study. Thus the results were obviated since no evaluable result that made it possible to draw any conclusion could be obtained. Usually, the maximum pain occurred on the same day of the surgery, while the inflammation reached its maximum point at 48 hours (13,42).

In our study, the incidence of these complications is estimated based on the personal subjective impressions, as in other similar studies, since we have hardly found any statistical studies on their frequency (23,42). During the first day of the surgery, there was a greater incidence of bleeding in those patients who had undergone semi-impacted third molar extractions, mainly due to the traumatism and to the closure by second intention of the surgical area. The bleeding on the third day was more frequent in patients who underwent impacted third molar extractions, probably due to the fact that the patient had done mechanical and erosion maneuvers with the teeth in the zone.

The presence of bleeding on the day of the surgery is related with semi-impacted third molar extractions (65.2%), and this may be because there is no edge to edge closures of the wound after the extraction of the third molar and posterior suture of the surgical area, on the contrary to that which occurs when the extraction is of an impacted third molar (34%) since the surgical area is sutured edge to edge. However, there is a greater percentage of bleeding after impacted third molar extraction (23.4%) on the second and third day after the surgery which can be due to some irritation or mechanical erosion maneuver of the surgical area by the patient. We have not observed a significant relationship between the type of analgesic and the presence or not of bleeding. We have verified that the presence of bleeding on the third day after the surgery appears in 19.1% of the cases after the impacted third molar surgery. This is because, in this type of surgery, there is closure of the edge to edge surgical bed and these cases are the ones that present greater bleeding, producing an accumulation of blood in the surgical area and in the adjacent tissues.

The most serious complication of the NSAIDs is gastrointestinal bleeding. In the moments following the drug intake, damage of the gastric epithelium is produced. Although it is asymptomatic, the risk of bleeding increases up to seven times when the treatment is prolonged for more than one week (41). In our surgical interventions, the administration of these drugs does not generally exceed three days. The gastroduodenal injuries are asymptomatic in 40% of the patients (31). In our study, we have had no reference to these injuries, although we have stressed it in the questioning.

The surgery performed evolves with inflammation, however we have not obtained statistically evaluable results nor have we found any study that analyzes the degree of inflammation of these operations. This inflammation picture can be explained because, in all the cases, the surgical procedure includes mucoperiostic flaps with discharges. This causes a greater traumatism of the soft tissues, that can reach the back of the vestibulum and thus there is greater local edema in the post-operative phase, giving rise to inflammation and acute pain.

CONCLUSIONS

1. Dexketoprofen Trometamol is more effective in the first hours after the surgery and its analgesic duration is 5.30 hours, while the analgesic duration of Ibuprofen is 6 hours after its administration.

2. Ibuprofen takes longer to have an effect (orally, one to two hours in reaching its maximum plasma concentration), however its analgesic duration is longer in time (from 6 to 8 hours).

3. Due to its indication for moderate pain, characteristic of oral surgical interventions, and its properties as rapid action analgesic, its potent anti-inflammatory action and reduced side effects, we can consider Dexketoprofen Trometal as a drug of choice for oral surgical interventions.

REFERENCES

1. Winter L, Bass E, Recant B, Cahaly JF. Analgesic activity of ibuprofen in postoperative and surgical pain. Oral Surg 1978;45:159-66.         [ Links ]

2. Cooper SA, Beaver WT. A model to evaluate mild analgesics in oral surgery outpatients. Clin Pharmacol Ther 1976;20:241-50.         [ Links ]

3. Cooper SA. Models for clinical assesment of oral analgesics. Am J Med 1983;75:24-9.         [ Links ]

4. Capuzzi P, Montebugnoli L, Vaccaro MA. Extraction of impacted third molars. A longitudinal prospective study on factors that affect postoperative recovery. Oral Surg Oral Med Oral Pathol 1994;77:341-3.         [ Links ]

5. Bagán JV, López JS, Valencia E, Santamaría J, Eguidazu I,Horas M, et al. Comparación clínica de Dexketoprofeno Trometamol y Dipirona en el dolor Dental Postoperatorio. J Clin Pharmacol 1998;38:55S-64S.         [ Links ]

6. Cooper SA. Five studies on Ibuprofen for postsurgical dental pain. Am J Med 1984;77:70-7.         [ Links ]

7. Gay C, Planas E, Donado M, Martínez JM, Artigas R, Torres F, et al. Eficacia analgésica de dosis bajas de dexketoprofeno en el modelo de dolor dental. Clin Drug Invest 1996;11:320-30.         [ Links ]

8. May N, Epstein J, Osborne B. Selective COX-2 inhibitors: A review of their therapeutic potential and safety in dentistry. Oral Surg Oral Med- Oral Pathol 2001;92:399-405.         [ Links ]

9. McGurk M, Robinson P, Rajayogeswaran V, De Luca M, Cassini A, Artigas R, et al. Clinical comparison of Dexketoprofen Trometamol, Ketoprofen and placebo in postoperative dental pain. J Clin Pharmacol 1998;38:46S-54S.         [ Links ]

10. Moore PA, Hersh EV. Celecoxib and Rofecoxib: The role of COX-2 inhibitors in dental practice. JADA 2001;132:451-6.         [ Links ]

11. Turek MD, Baird WM. Double blind parallel comparison of ketoprofen (Orudis), acetaminophen plus codeine, and plaebo in postoperative pain. J Clin Pharmacol 1988;28:23-8.         [ Links ]

12. Olmedo MªV, Vallecillo M, Gálvez R, Lillo E, Cañedo P. Estudio del dolor postextracción. Características y medición. Rev Eur Odontoestomatol 1995;7: 241-6.         [ Links ]

13. Romero Ruiz MM, Infante Cossío P, Torres Lagares D, Serrano González A, Gómez de la Mata Galiana J, Gutiérrez Pérez JL. Tendencias actuales en el control del dolor y la inflamación tras la extracción de terceros molares incluidos (parte 1). Rev Eur Odontoestomatol 2001;13:261-6.         [ Links ]

14. Peñarrocha M. Dolor Orofacial: Etiología, diagnóstico y tratamiento, Barcelona: Masson Ed; 1997. p. 20-4.         [ Links ]

15. Hargreaves KM, Troullos ES, Dionne RA. Bases farmacológicas para el tratamiento del dolor agudo. Clin Odontol Norteam 1987;4: 833-5.         [ Links ]

16. Albrecht C, Van Aken H. Paracetamol and propacetamol for postoperative pain: contrasts to traditional NSAIDS. Ball Clin Anaesthesiol 1995;9:563-6.         [ Links ]

17. Baños J E, Bosch F, Toranzo I. La automedicación con analgésicos. Estudio en el dolor odontológico. Med Clin 1991;96:248-51.         [ Links ]

18. Bascones A, Manso FJ. Infecciones Orofaciales: Diagnóstico y tratamiento. Ed. Avances; 1994. p. 45-6.         [ Links ]

19. Bascones A, Manso FJ. Dolor Orofacial: Diagnóstico y tratamiento. Ed. Avances; 1997. p. 385-90.         [ Links ]

20. Bascones A, Bullón P, Castillo JR, Machuca G, Manso FJ, Serrano JS. Bases farmacológicas de la terapeútica odontológica. Ed. Avances; 2000. p. 341-58.         [ Links ]

21. Lasagna L. The management of pain. Drugs 1986;32:1-7.         [ Links ]

22. Peñarrocha M, Peñarrocha Mª. Reflexiones sobre el dolor dental. Av Odontoestomatol 1995;11:13-8.         [ Links ]

23. Peñarrocha M, Marco MD, Sanchís JM, Estarelles R, Gay C, Bagán JV. Estudio del postoperatorio tras la extracción quirúrgica de 100 terceros molares inferiores impactados en relación a la dificultad del acto quirúrgico. Av Odontoestomatol 2000;16:377-82.         [ Links ]

24. Santamaría J, Artegoitia MI. El dolor en la cirugía del tercer molar inferior e implantología. Av Odontoestomatol 1995; 11 (suppl A): 67-79.         [ Links ]

25. Towbridge O. Review of dental pain: Histology and Physiology. J Endo 1986;12:142-5.         [ Links ]

26. McGurk M, Robinson P. Clinical comparison of Dexketoprofen Trometamol, Ketoprofen and Placebo in postoperative dental pain. J Clin Pharmacol 1998; 38:46-54.         [ Links ]

27. Meredith TJ, Vale JA. Non-narcotic analgesics: problems of overdosage. Drugs 1986;32:177-205.         [ Links ]

28. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. Br J Anaesth 2002;88:72-7.         [ Links ]

29. Morrison BW, Fricke J, Browne J, Yuan W, Kotey P, Mehlish D. The optimal analgesic dose of Rofecoxib: Overview of six randomized controlled trials. JADA 2000;131:1729-37.         [ Links ]

30. Manso FJ, Bascones A, Maqueda MJ, Vadillo JM. Estudio controlado sobre la eficacia y tolerabilidad de ibuprofen-arginina vs. Aceclofenaco en el dolor post-extracción quirúrgica de molares inferiores. Av Odontoestomatol 1996;12:493-6.         [ Links ]

31. Llorente MJ. Specific types of NSAIDS and relative risk of UGIB. Bri J Rheumatol 1998;37:115.         [ Links ]

32. Goodman y Gilman. Las bases farmacológicas de la terapéutica. Ed. Panamericana; 1986. p. 75-85.         [ Links ]

33. Royer GL, Sekman CE, Welshman IR. Safety Profile: Fifteen Years of Clinical Experience with Ibuprofen. Am J Med 1984;77:25-34.         [ Links ]

34. Malenco JL, Pérez M., Navarro FJ, Martínez FJ, Beltrán J, Salvatierra D, et al. A multicentre, randomised, double-blind study to compare the eficacy and tolerability of Dexketoprofen Trometamol versus Diclofenac in the symptomatic treatment of knee osteoarthritis. Clin Drug Invest 2000; 19:247-56.         [ Links ]

35. Gich I, Bayés M, Barbanoj MJ, Artigas R, Tost D, Mauleón D. Bioinversión del R(-)-ketoprofeno después de su administración oral a voluntarios sanos. Clin Drug Invest 1996;11:347-53.         [ Links ]

36. Mauleón D, Artigas R., García ML, Carganico G. Desarrollo clínico y preclínico del dexketoprofeno. Drugs 1996;52:24-46.         [ Links ]

37. McGurk M. Ensayo clínico doble ciego, aleatorizado, paralelo, para comparar dosis únicas de dexketoprofeno trometamol con ketoprofeno y placebo en pacientes con dolor dental moderado o severo tras la extracción del tercer molar impactado. Guy's Hospital, Londres. Datos archivo de Menarini.         [ Links ]

38. Otten JE. Estudio doble ciego, aleatorizado, paralelo para comparar la eficacia y seguridad de dosis únicas de dexketoprofeno trometamol 12.5 mg o 25 mg con placebo en pacientes con dolor dental moderado o severo tras la extracción del tercer molar impactado. University of Freiburg. Datos de archivo Menarini.         [ Links ]

39. Flórez J. Farmacología Humana. Ed Masson; 1992. p. 250-75.         [ Links ]

40. Kantor GT. Introduction: Ten-Year Update on Ibuprofen. Am J Med 1984; 77:1-2.         [ Links ]

41. Hyllested H, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracemtamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002;88:199-214.         [ Links ]

42. Infante P, Espín F, Mayorga F, Hernández JM, Rendón JI, Delgado MJ. Estudio prospectivo de los factores relacionados en la recuperación postoperatoria tras la exodoncia de terceros molares inferiores retenidos. Av Odontoestomatol 1995;11:569-72.         [ Links ]