A Randomized, Double-Blind, Placebo-Controlled Trial of Ibuprofen Lysinate in Comparison to Ibuprofen Acid for Acute Postoperative Dental Pain

Eligible study participants were healthy men and women (aged 18–60 years) scheduled to undergo outpatient surgical removal of one or more third molars, at least one of which was impacted in bone. To be eligible for inclusion, patients agreed not to take analgesics other than protocol-defined rescue analgesics during treatment, anti-inflammatory drugs, sedative-hypnotics, or antidepressants, tranquilizers, alcohol- or caffeine-containing beverages up to 6 h post-dose. Patients qualified for being treated with the test drugs when their baseline pain intensity (PI) exceeded 50 mm on a 100-mm visual analog scale (VAS).

Patients were excluded if they had used any analgesics, anti-inflammatory drugs, sedative-hypnotics, or antidepressants, tranquilizers, alcohol- or caffeine-containing beverages from midnight of the night prior surgery. Additionally, patients were ineligible to participate if there was the acute purulent inflammation in the area of the planned bone-impacted third molar removal; another acute or chronic painful physical condition; history or presence of significant organ disease. Other exclusion criteria were the presence, or recent history, of active peptic ulcer disease or gastrointestinal bleeding, any clotting or hematogenesis disorder, and, in women, pregnancy or breastfeeding. Finally, patients were excluded if they had any other disease or condition that may interfere with study assessments as judged by the investigator or were taking part in any other clinical trial or had participated in a clinical trial within the previous 3 months.

Patients were randomized in a 2:2:1 ratio to ibuprofen lysinate 683 mg (corresponds to ibuprofen acid 400 mg), ibuprofen acid 400 mg, or placebo, using random permutated blocks. No detailed information (including block size) was available to the investigators, who were provided with random numbers from a pseudorandom number generator.

Patients were randomized on the day of surgery (day 1) and received a single dose of the study medication once the effects of the local anesthetic effects had worn off, as long as the PI was ≥ 50 mm on the pain VAS. Because ibuprofen lysinate and ibuprofen acid tablets are not identical in shape and weight, dummy tablets of the alternative agent were used to maintain blinding. In the ibuprofen lysinate group, patients received ibuprofen lysinate 683 mg and placebo of the ibuprofen acid tablet as dummy. In the ibuprofen acid group, patients received ibuprofen acid 400 mg and placebo of the ibuprofen lysinate tablet as dummy, and in the placebo group, patients received both placebo tablets. The medication was presented to the patient by the study nurse (not the investigator) in indistinguishable vials containing two tablets in separate blister packs to maintain blinding. The nurse watched the patient take the medication with water to ensure compliance. The patients and investigators were blinded to the study medication. Patient assessments were undertaken at regular intervals for 6 h after drug administration, and patients returned to the study center 2 days later (day 3) for further assessment of efficacy and safety. Patients who did not achieve adequate pain relief were permitted to take rescue medication (paracetamol 500–1000 mg).

The primary objective was to demonstrate that: (1) ibuprofen lysinate is superior to placebo in overall analgesic efficacy; (2) ibuprofen lysinate is non-inferior to ibuprofen acid (the active comparator) in overall analgesic efficacy; and (3) ibuprofen lysinate is superior to ibuprofen acid in the onset of action. Secondary objectives were to assess the superiority of ibuprofen acid over placebo in total pain relief (TOTPAR), and other parameters of efficacy, such as global assessment, time to pain half gone, time to any pain relief, time to meaningful pain relief, and sum of the pain intensity difference (SPID).

Patients were asked to rate their pain relief (PAR) and PI at regularly scheduled intervals (15, 30, 45, 60, and 90 min and 2, 3, 4, 5, and 6 h). PAR was rated on a standard five-point scale (where 0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete pain relief), while PI was rated on a 100 mm VAS (boundaries of the scale were marked none and severe). The primary efficacy endpoint was the TOTPAR comprising the weighted sum of the PAR scores at 6 h. The difference of one point in PAR represents the minimum detectable pain difference for a patient. Thus, a value of 6 for TOTPAR was the minimum detectable pain difference over the 6-h observation period. The equivalence limit was set a priori to − 3 (i.e., TOTPAR difference). The PI difference (PID) was calculated by subtracting the pain intensity at each time point from the baseline pain intensity. The overall SPID was calculated as the weighted sum of the PID scores at 6 h post-dose. Time to pain half gone was calculated from the VAS pain intensity assessment.

Patients were asked for global assessment of study medication at the conclusion of the 6-h study period (or when the patient took rescue medication or at the time of premature termination, depending on what occurred first). Patients rated their pain medication on a five-point scale in response to the question “How would you rate the study medication you received for pain?”, where 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. Patients were asked to record the onset of analgesia by noting the time to any pain relief (defined as the first perceptible pain relief), and time to meaningful pain relief, irrespective of the given (regular) time intervals for pain assessment. The use of rescue medication was also recorded.

The safety of ibuprofen lysinate and ibuprofen acid relative to placebo was assessed based on the incidence of adverse events (AEs) reported by patients on the day of surgery and at the follow-up visit. AEs were elicited using a standard non-misleading question such as “How did you feel since the last visit?”. In addition, any signs or symptoms were observed.

The study aimed to enroll 350 patients. For the power analysis, it was assumed that both active treatments have the same overall analgesic efficacy and that the aim was to reject the null hypothesis of inferiority of the test drug. Based on published data, true TOTPAR was assumed to be 14 with a standard deviation of 7. Provided that non-inferiority margin is − 3, 116 evaluable subjects per treatment group were required to achieve power of 90% at the α = 0.05 significance level (two-sided). A surplus of 20% was added because of possible protocol violators and the total number was rounded up to 140 enrolled subjects in either active treatment group [11‐14]. With 140 patients in each active treatment arm, the minimum detectable difference with power of ≥ 80% was about 10 mm.

The first hypothesis was superiority of ibuprofen lysinate over placebo, based on the lower limit of the 95% confidence interval (CI) for the difference in TOTPAR between the groups being greater than 0. The second hypothesis was that ibuprofen lysinate was non-inferior to ibuprofen acid, demonstrated by the two-sided 95% CI for the treatment difference being entirely to the right of the non-inferiority margin (i.e., − 3). The third hypothesis was that ibuprofen lysinate has a superior onset of action to ibuprofen acid, shown if the lower limit of the 95% CI for the treatment difference in PAR at 45 min post-dose was greater than 0. Hierarchical statistical testing was employed whereby subsequent analyses were conducted only if the previous hypothesis was proven using these criteria.

The primary analyses were undertaken on the intention-to-treat (ITT) population, which comprised all randomized patients who received the study medication and had at least one post-baseline measure of PAR and PI. Secondary analyses were undertaken on the per-protocol population, which included all members of the ITT set who did not have a major protocol violation. The safety analysis set comprised all patients who received the study medication.

The study was sponsored by Zentiva Group a.s., which held the data during the study. The authors had complete access to the data after unblinding. The data reported here were those available to the authors as of March 13, 2008. The study results were publicly available at https://​www.​clinicaltrialsre​gister.​eu.

A total of 381 patients were screened, and 351 were randomized and received study medication (Fig. 1). Table 1 shows the number of patients in the predefined datasets. Baseline demographics and clinical characteristics were not significantly different between the groups (Table 2). Patients were aged 18–60 years (mean 28 years), and the majority (n = 210 [59.8%]) were female (Table 2). Most patients (73.2%) were having a single molar extracted.

Both active treatments reduced pain beginning at 15 min after administration and lasting for at least 6 h (Fig. 2). Both ibuprofen formulations were significantly more effective than placebo in achieving pain relief over 6 h (TOTPAR) and at 45 min post-administration (Table 3). The first primary hypothesis that ibuprofen lysinate was significantly more effective than placebo at providing pain relief over 6 h was demonstrated, as was the second primary hypothesis that ibuprofen lysinate was non-inferior to ibuprofen acid for pain relief over 6 h (Table 3). The third hypothesis (that ibuprofen lysinate was superior to ibuprofen acid for pain relief at 45 min, and therefore associated with a more rapid onset of action) was not confirmed. Similar results were obtained in the analyses of SPID and PID at 45 min (Table 3).

Fewer patients taking ibuprofen than placebo required rescue medication. In the ibuprofen lysinate and ibuprofen acid arms, 21 of 140 patients (15%) and 20 of 139 patients (14.4%), respectively, took rescue medication, compared with 21 of 71 patients (29.6%) in the placebo arm.

Time to any pain relief, to meaningful pain relief, and to pain half gone are presented in Table 4. There was no significant difference between the two ibuprofen formulations in the time to any pain relief (p = 0.6618), time to meaningful pain relief (p = 0.8630), and time to pain half gone (p = 0.9133).

Patients’ global assessment of efficacy showed significantly higher ratings with either of the active treatments compared with placebo (p < 0.05 for each comparison). Treatment was rated as “good”, “very good”, or “excellent” by 75.0% of patients receiving ibuprofen lysinate, 80.5% of patients receiving ibuprofen acid, and 31.0% receiving placebo. There was no significant difference between ibuprofen lysinate and ibuprofen acid (p > 0.05).

All treatments were well tolerated, and all reported AEs were of mild to moderate intensity. Two patients in the ibuprofen lysinate group (1.4%) developed edema; other AEs occurring in one patient each (0.7%) were oral administration complication (i.e., difficulty swallowing the tablets), pain, wound complication, wound dehiscence, seroma, facial swelling, alveolar osteitis, and hematoma. Similarly, in the ibuprofen acid arm, two patients (1.4%) developed edema and one each (0.7%) developed procedural pain, post-procedural edema, headache, paresthesia, hypoesthesia, nausea, dysphagia, increased body temperature, epistaxis, and facial swelling. None of the AEs in either active treatment arm was considered by investigators to be treatment-related. No AEs were reported by patients receiving placebo.

The number of molars having extracted can influence the level of pain and possibly efficacy and safety. In our study, most patients were having a single molar extracted. Between the study groups, patients with one or two tooth extractions did not differ significantly and thus the effects on efficacy and safety were considered to be balanced.