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Medicina Oral, Patología Oral y Cirugía Bucal (Ed. impresa)

versión impresa ISSN 1698-4447

Med. oral patol. oral cir. bucal (Ed.impr.) vol.9 no.5  nov./dic. 2004


Analgesic efficacy of diclofenac sodium versus ibuprofen following surgical extraction of impacted lower third molars



-Objective: An evaluation is made of the analgesic efficacy of diclofenac sodium versus ibuprofen after impacted lower third molar surgery.
-Study design: The patients were randomly assigned to one of two groups (ibuprofen or diclofenac). The difficulty of third molar surgery, performed under local anesthesia, was assessed by the degree of inclusion involved. The recorded study variables were pain intensity and the need for rescue medication during one week. The recordings were made once a day at the same time, using a patient-completed questionnaire.
-Results: Eighty-one patients were finally included in the study (87.1%). The results were similar in the first 48 postoperative hours in both groups, though on the third day the diclofenac group tended to show higher pain scores - the differences being nonsignificant, however (p>0.05). This tendency was also reflected by an increased need for rescue medication and the consumption of a larger number of tablets in the diclofenac group.
-Conclusions: There were no statistically significant differences in analgesic efficacy between diclofenac sodium and ibuprofen, though the former was associated with an increased need for supplementary medication in the first two postoperative days (p>0.05).

Key words: Diclofenac sodium, ibuprofen, analgesic-antiinflammatory drugs, third molar surgery.


Pathology induced by impacted lower third molars is very common, and is attributable to a singular series of embryologic and anatomical circumstances. The resulting clinical manifestations usually led to extraction of the impacted tooth (1-4). The postoperative period is characterized by pain, trismus and inflammation as the most frequent complications (5,6). Accordingly, an ideal drug substance for administration after the surgical removal of an impacted lower third molar should alleviate pain, reduce inflammation and trismus, facilitate healing and cause no undesirable side effects (7).

Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to be effective for the management of mild to moderate postoperative pain (8), and are often used in combination with opioids for the treatment of more severe pain (9,10). Most NSAIDs act primarily by inhibiting the enzyme cyclooxygenase (COX), thereby preventing local prostaglandin synthesis (11). Most of these drug substances inhibit both isoforms of the enzyme (i.e., COX-1 and COX-2), and specific action upon COX-1 is considered to be responsible for the undesirable effects associated with NSAIDs. The latter are even believed to exert central action, as suggested by the studies of Jurna and Brune (12).

Pain models designed for application in the context of clinical trials require the prior induction of sufficient background pain, a low placebo effect, a homogeneous study population, and good patient cooperation. Dental pain models meet many of these conditions (13). As a result, pain following the surgical extraction of impacted lower third molars has been widely used to explore the analgesic and antiinflammatory efficacy of many drugs. One of the main reasons why this particular pain model is widely used is that it allows the predictable development of pain and inflammation in young patients without systemic pathology, in whom the surgical extraction of impacted lower third molars is indicated (14).

Surgery of impacted lower third molars is known to cause more intense pain than any other oral surgical procedure (7). In effect, the surgical extraction of lower third molars induces postoperative pain peaking in intensity after 6 hours (15) - the level of pain reached being sufficient to discriminate the efficacy of different analgesic substances (13).

The aim of such clinical trials is to determine the efficacy of pain relief, with a description of the corresponding drug pharmacokinetic and pharmacodynamic properties, and the definition of possible side effects attributable to the medication prescribed (13). The efficacy variables considered are pain intensity and relief, the estimation of total analgesia, the peak analgesic effect, and the start and duration of analgesic action (16). One of the most widely used pain-killing drugs is ibuprofen, which is currently used as positive control in most clinical trials of this kind. Due to the great number of analgesic-antiinflammatory drugs presently found on the market, and the reasonable doubts over which specific pharmacological group to be chosen for administration after the surgical extraction of third molars, we conducted a series of studies to compare the efficacy of different active drug substances versus ibuprofen.

In this context, diclofenac sodium is a well known NSAID that has been used for many years in Rheumatology, since it offers a good combination of efficacy and tolerance (17). Following surgical extraction of a third molar, diclofenac sodium has been shown to afford effective pain and inflammation control, as well as good patient tolerance (17). Double-blind placebo controlled studies have shown diclofenac to exert a dose-dependent analgesic effect (18), based on the inhibition of prostaglandin synthesis (19) - though it is admitted that other mechanisms of action may be involved, since high plasma beta-endorphin concentrations are known to intervene (20). The present study assesses the analgesic efficacy of diclofenac sodium in comparison with ibuprofen, following the surgical extraction of impacted lower third molars in the Service of Oral Surgery (Barcelona University Dental Clinic, Spain).


A protocol was designed to conduct a prospective, randomized double-blind controlled phase IV study involving the surgical extraction of an impacted lower third molar in each patient, following the obtainment of informed consent. All surgical interventions were carried out by three surgeons of similar experience between March 2000 and April 2001, in the context of the Master of Oral Surgery and Implantology (School of Dentistry of the University of Barcelona, Spain). The postoperative controls were in turn carried out by an independent examiner. All lower third molars were extracted under local anesthesia with 4% articaine and 1:100,000 adrenalin (Articaína-Inibsa®), using a standardized technique (21). The duration of surgery was defined as the time elapsed from mucosal incision to last suture placement.

The patients were randomly assigned to one of two groups, based on a 10-element random permutations table: (a) control (treated with ibuprofen) or (b) experimental group (treated with diclofenac sodium).

-Inclusion criteria:

• Age: 18-40 years
• Degree of dental inclusion between 5 and 7 according to the scales of Pell-Gregory and Winter (Figures 1 and 2)(22)
• Absence of systemic disease
• Absence of local clinical manifestations in relation to third molar inclusion
• Patient capacity to complete the questionnaires correctly

-Exclusion criteria:

• Surgical time in excess of 45 minutes
• Patient failure to comply with the prescribed medication
• Patient failure to present to the programmed postoperative control visits
• Patients with systemic disease
• Patients with blood dyscrasia or coagulation disorders
• Pregnant women
• Consumption of drugs of abuse
• Patients having taken some medication in the previous 24 hours


• Antibiotic: amoxicillin 750 mg every 8 hours for 4 days
• Analgesic-antiinflammatory medication:

Ibuprofen 600 mg every 8 hours during 4 days
Diclofenac sodium 50 mg every 8 hours during 4 days

• Rescue analgesia: paracetamol/codeine 325/15 mg, two tablets as required
• Antiseptic: 0.12% chlorhexidine mouthrinse 3 times a day for 7 days

Treatment with the antibiotic and NSAID corresponding to each group was started on a prophylactic basis immediately after surgical extraction. The patients were instructed to take the medication with some food or drink, rather than under fasting conditions. Rescue analgesia was only to be used when the prescribed NSAID failed to afford good pain control in the hours following administration of the drug. The patients likewise received the questionnaires to be completed in the course of the following 7 days.

The following study variables were recorded:

(a) Pain intensity. The patients scored perceived pain on a 100-mm visual analog scale (VAS), the extremes of which corresponded to “absence of pain” and “worst pain imaginable”. The recordings were to be made between 21:00 and 23:00 p.m. during the 7 days after surgical extraction.

(b) Rescue medication. The patients were instructed to record the need for rescue medication (in terms of the number of tablets used) on a daily basis.

Postoperative controls were carried out after 48 hours and 7 days by an independent examiner unrelated to the study. At the control 48 hours after extraction, the postoperative course was assessed, and any complications were registered. In addition, patient instructions regarding correct medication were reinforced. The control visit after 7 days coincided with removal of the sutures and retrieval of the study questionnaires.

Statistical analysis

The statistical analysis of the results was made using the SPSS version 10 statistical package under Microsoft Windows (University of Barcelona license). The Kolmogorov-Smirnov and Shapiro-Wilkes tests were applied to assess normal distribution of the variables. Comparison of the mean pain scores was carried out by analysis of variance (ANOVA) for repeat measures. Statistical significance was accepted for p<0.05.


A total of 93 patients were operated upon, while 12 failed to comply with the inclusion criteria and were excluded from the study - i.e., 81 subjects were finally included to the effects of analysis (87.1%). The age range in both groups was between 18 and 35 years, with an average of 23.2 years (SD ± 3.9); 58.4% were females and 41.6% males. The sex distribution was similar in both groups. The variables relating to age, body weight and surgical time were likewise similar in both groups, as was the mean surgical extraction difficulty involved (between 5 and 7 on the scales of Pell-Gregory and Winter). As to the prescribed medication, 40 patients (49.4%) were assigned to diclofenac sodium, and 41 patients (50.6%) to the ibuprofen treatment arm of the study.

For each day and group, mean patient perceived pain was rated based on a 100-mm VAS. Accordingly, the first two recordings corresponding to the first 48 hours post-extraction showed similar mean scores for both groups: 41 and 37 mm the first day, and 26 and 27 mm the second day for diclofenac and ibuprofen, respectively (Figure 3).

However, normality testing (Kolmogorov-Smirnov and Shapiro-Wilkes tests) detected irregularities regarding the normal distribution of this variable in each group and on each day. Thus, while the values recorded were similar in the first 48 postoperative hours, starting on day 3 the diclofenac group began to show higher pain scores - though without statistically significant differences (p>0.05), according to the results of the ANOVA for repeat measures.

This tendency towards increased pain intensity in the postoperative period in the diclofenac group was also reflected by an increased need for rescue medication and the consumption of a larger number of tablets in the diclofenac group, particularly in the first 48 hours - though here again the differences were not significant versus the ibuprofen group. On the first postoperative day the patients requiring rescue medication in the diclofenac group outnumbered those who did not.

Only one patient in the diclofenac group required 6 tablets a day during the first two days. The rest of the patients used 2-4 tablets a day during the 7 days of the study. In this sense, and has been mentioned above, while the patients administered diclofenac tended to require more rescue medication, there were no statistically significant differences with respect to the ibuprofen group (p>0.05).


One of the problems of evaluating the analgesic and antiinflammatory efficacy of a given drug is represented by the posology involved. In this context, the practice of initiating administration preoperatively is particularly controversial. The current tendency is to start treatment at an earlier stage than in the past, since it has been shown that postoperative pain can be avoided almost entirely through analgesic premedication (23). The prophylactic administration of analgesics has been used in clinical trials to assess postoperative pain, inflammation and oral aperture (24-26). In our case, and considering that the surgical extractions implied a degree of ostectomy due to the existing molar inclusion, it was to be assumed that none of the patients would be without postoperative pain. Hence, to a degree, medication was provided on a prophylactic basis - prior to the appearance of pain, and on ethical grounds.

Another important factor to be taken into account is the evaluation period. In effect, with the introduction of long-acting analgesics, prolonged observation periods have become necessary in the context of single-dose studies (27).

The severity of pain following the surgical extraction of lower third molars does not appear to be related to the type of incision performed, the magnitude of the ostectomy, or the need for dental sectioning - though some studies suggest that wound suturing does influence the appearance of pain (28), and it has been postulated that patient sex is the only factor that tends to be statistically significant in this context (29). This is in concordance with the results obtained in other studies which have shown women to refer greater pain based on VAS scoring after third molar surgery (30,31). Nevertheless, these results differ considerably from those obtained by Hansson et al. (32). The influence of patient sex upon postoperative pain levels is thus seen to be controversial, though it seems logical that the increased anxiety shown by women undergoing third molar surgery effectively may have some influence upon the postoperative course (33). In our case, 58.4% of the patients were females and 41.6% males, and the statistical analysis revealed no significant intra- or intergroup differences between sexes in terms of postoperative pain scoring (p>0.05).

Few studies have analyzed and compared the analgesic efficacy of diclofenac sodium. The plasma peak of the drug is reached 1.5-2 hours after oral administration (34,35). Following the surgical extraction of impacted third molars, diclofenac sodium has been shown to afford effective control of the pain and inflammation, and patient tolerance is good (17). In addition to inhibiting prostaglandin synthesis in peripheral tissues, diclofenac interacts with the synthesis of nitric oxide and endogenous opioids in the central nervous system (36,37). Breivik et al. showed that when diclofenac is combined with acetaminophen (paracetamol) with or without codeine, superior and more prolonged pain control is achieved, with fewer side effects, versus the administration of diclofenac alone, or of acetaminophen with or without codeine (38). This is only understandable if it is accepted that diclofenac and paracetamol possess different mechanisms of action upon the nociceptive nerve endings and at various neuroanatomical levels. The main problem of NSAIDs used to control postoperative pain is a decrease in renal function and the possibility of hemostatic complications (39). Moreover, diclofenac, in the same way as other NSAIDs, inhibits thromboxane (TXA2) production, reduces platelet aggregation, and increments bleeding - as has already been commented in the Introduction (40,41).

At present, most clinical trials comparing the analgesic efficacy of different drugs make use of ibuprofen as reference substance, due to its analgesic capacity, good tolerability, and near total lack of complications or side effects when administered following third molar surgery (42-47). Our study did not include a placebo group, since inclusion of such a group would be questionable on ethical grounds, and prior studies moreover have already confirmed the efficacy of diclofenac (48) and ibuprofen (49,50) versus placebo in a dental pain model. In this context, soluble ibuprofen formulations afford faster analgesia than solid formulations (50).

Single-dose clinical trials have confirmed the analgesic efficacy of ibuprofen. The latter has been shown to exhibit a poor dose-dependent response in the control of dental pain when administering single doses of 100, 200 and 400 mg (51), and 400, 600 and 800 mg of ibuprofen (52), i.e., the response is unrelated to the dose administered.

Different studies have shown that the analgesic efficacy of ibuprofen does not increase with doses above 400 mg - probably as a consequence of an analgesic ceiling effect (42,52). In another study of the dose-dependent analgesic response of ibuprofen (53), the administration of low doses of the drug was seen to be insufficient to control postoperative pain - a 400 mg dose being preferable in view of the long duration of the analgesic effect obtained (49,54). Nevertheless, no significant relation has been demonstrated between the analgesic efficacy of ibuprofen and the pharmacokinetic characteristics of the drug (absorption, distribution, metabolization and excretion)(54), despite the fact that other authors have reported a correlation between pain intensity and the plasma concentrations of ibuprofen following single doses of 400, 600 and 800 mg (52). It has furthermore been shown that ibuprofen is found as a racemic mixture of R(-) and S(+) enantiomers; thus, it has been estimated that between 52-63% of the R(-) form undergoes stereospecific conversion to the S(+) form (55,56) - the antiinflammatory and analgesic activity of ibuprofen being though to correspond exclusively to the S(+) enantiomer (57).

Nørholt (13) and Nørholt et al. (58) investigated whether the analgesic efficacy of ibuprofen can be assessed based on trismus, bite force and pressure algometry. These authors concluded that such functional parameters are related to the analgesic efficacy of ibuprofen. However, as was already pointed out by Mehlish (59), the above mentioned studies were fundamented on the biased starting hypothesis that pain is the cause underlying the functional impotency - when it appears more logical to assume functional impotency to be a normal physiological response to traumatism (59).

It can therefore be considered that 400 mg of ibuprofen are sufficient to control the postoperative pain following impacted third molar surgery. On establishing statistical comparisons to contrast the analgesic efficacy of two drugs, the dose in question was found to be more effective than 150 mg of aceclofenac in the context of single-dose surveys (60). In our study we found no statistically significant differences in terms of the intensity of pain between 50 mg of diclofenac sodium and 600 mg of ibuprofen, though the patients in the diclofenac group showed a greater tendency to make use of supplementary medication in the first two days.

Due to the poor dose-response relation characterizing NSAIDs, a dose increment above the recommended dose would yield little in terms of increased analgesic action, while in contrast the incidence of adverse effects would grow. This limitation of the analgesics and of the available drug combinations generates a therapeutic dilemma, since a suboptimal dose must be prescribed in order to avoid the possible side effects that may appear. The traditional approach used to overcome this limitation is to combine the therapeutic dose of a NSAID with a minimum opioid dose, affording added analgesia without a parallel increase in adverse effects. However, no significant differences have been observed on adding 15 mg of codeine to 200 mg of ibuprofen (61), or on supplementing 300 mg of ibuprofen with 20 mg of codeine (62). Nevertheless, on adding 60 mg of codeine to 400 mg of ibuprofen, and although pain control failure was noted with the initial dose, increased analgesia was recorded during the subsequent three days - with only a modest increase in side effects (63). The combination of 10 mg of oxycodone with 400 mg of ibuprofen yielded added analgesia, though only in the earliest postoperative phases, when the R(-) enantiomer undergoes steroeoconversion to the S(+) form. The difference was not detectable beyond the first three hours after surgery (64). It should be pointed out that this added analgesic effect was obtained at the expense of a high rate of side effects at central nervous system level (drowsiness and vomiting). In order to avoid this, the achievement of preventive analgesia in the model of impacted third molar surgery is proposed. Furthermore, added analgesia can also be achieved by using a long-acting local anesthetic such as ethidocaine or bupivacaine (65).

Although the described pain model is appropriate for clinical trials such as those commented above, the latter do not take into account the great variability among patients in terms of their response to the surgical intervention, the analgesic actions of the drug and sensitivity to the associated side effects. In most studies, the approach used is fixed-dose administration via the oral route, and thus the exact dose in mg/kg body weight varies with the patient body mass index (BMI). Pharmacokinetic differences can also contribute to the observed variability in patient response.


No statistically significant differences have been recorded in terms of the analgesic efficacy of diclofenac sodium with respect to ibuprofen, though an increased tendency to use more supplementary medication was observed during the two first days of the postoperative period in the diclofenac group; statistical significance was not reached, however (p>0.05).


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