PAIN 152 (2011) 632642

www.elsevier.com/locate/pain

A randomised, ve-parallel-group, placebo-controlled trial comparing the efcacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain
Stephen E. Daniels a,, Michael A. Goulder b, Sue Aspley c, Sandie Reader d
a

Premier Research, Austin, TX, USA Worldwide Clinical Trials, Nottingham, UK Reckitt Benckiser Healthcare UK Ltd, Hull, UK d Clearcut Clinical Consulting, Nottingham, UK
b c

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

a r t i c l e

i n f o

a b s t r a c t
Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5arm, parallel-group, placebo-controlled, randomised, single-dose study designed to compare the efcacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg; 2 tablets of ibuprofen 200 mg/codeine 12.8 mg; 2 tablets of paracetamol 500 mg/ codeine 15 mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12 hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically signicantly more efcacious than 2 tablets of placebo (P < 0.0001) and paracetamol/codeine (P 6 0.0001); furthermore, 2 tablets offered signicantly superior pain relief to ibuprofen/codeine (P = 0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically signicantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain. 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.

Article history: Received 19 April 2010 Received in revised form 29 October 2010 Accepted 6 December 2010

Keywords: Dental pain Surgery Codeine Paracetamol Ibuprofen Analgesia

1. Introduction Ibuprofen and paracetamol are analgesic compounds commonly used for treating mild to moderate pain [6,11,12]. For the relief of more severe pain, combination analgesia is often recommended, as the combination of analgesics with different modes of action has the potential to optimise efcacy and tolerability [35]. Codeine has been shown to confer additional efcacy when used in combination with either ibuprofen or paracetamol in the short to medium term [14,17,37] and ibuprofen/codeine combinations have been investigated for the relief of stronger pain, primarily after dental or other surgery [9,11,15,18,22,23,31,32,34,41]. Due to adverse effects associated with codeine, such as drowsiness, constipation, respiratory depression, emesis, and urinary retention, many
Corresponding author. Address: Premier Research, 3200 Red River, Suite 300, Austin, TX 78705, USA. Tel.: +1 512 287 6401; fax: +1 512 320 0313. E-mail address: stephen.daniels@premier-research.com (S.E. Daniels).

patients either cannot, or prefer not, to take codeine. In addition, due to genetic polymorphisms in the genes responsible for the metabolism of codeine, patients range from poor metabolisers, who may not experience any pain relief, to ultra-extensive metabolisers, who can experience intoxication with codeine use [5,13,36].Therefore, there is a need to nd an alternative effective analgesic for use in combination therapy. Ibuprofen (a nonsteroidal antiinammatory drug [NSAID]) and paracetamol differ in their modes of action. Ibuprofen acts by inhibition of cyclooxygenase enzymes (COX-1 and COX-2) and subsequent synthesis of prostaglandins and related compounds at peripheral sites within injured tissue [39]. In contrast, the mode of action of paracetamol, although not completely understood, appears to be related to the inhibition of a sub-class of cyclooxygenase enzyme isoforms in the central nervous system [7]; however, it has also been shown to cause COX-2 inhibition and may act as a weak NSAID when given at high doses [20].

0304-3959/$36.00 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. doi:10.1016/j.pain.2010.12.012

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Peak serum levels occur within 1 to 2 hours of administration for ibuprofen and between 30 minutes and 2 hours for paracetamol [14]. Unlike ibuprofen, paracetamol has no antiinammatory activity and is observed to offer less effective analgesia than NSAIDs in some indications, including dental pain [35,37]. These differences between ibuprofen and paracetamol, in their modes of action and related therapeutic effects, suggest that they may complement each other and that enhanced analgesic effect, without increased toxicity, may be obtained with combination therapy over monotherapy. The co-administration of ibuprofen and paracetamol has been investigated in a number of studies and shown to be effective, particularly for the relief of postoperative pain [16,21,29,30,40]. The study described here was designed to compare the efcacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination and a paracetamol/codeine combination using the dental impaction pain model, which is a validated and reproducible acute pain model [6,11,12,24,25,28,29]. Previously, this novel combination tablet has demonstrated efcacy over comparable doses of monotherapy in the dental impaction pain model [26,27], and the pharmacokinetic prole of either drug was found not to be signicantly altered when administered in a xed-dose combination tablet, except for an enhancement in the rate of absorption of paracetamol, which may potentially offer therapeutic benets in relation to onset of analgesia [38]. 2. Methods 2.1. Design This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose, 3-site study to compare the efcacy and tolerability of different analgesic combinations for postoperative dental pain following third molar extraction. The study was conducted in accordance with the Declaration of Helsinki (South Africa, 1996), as referenced in European Union Directive 2001/20/EC. It complied with International Conference on Harmonisation, Good Clinical Practice, and the Code of Federal Regulations (CFR) of the US Food and Drug Administration (21 CFR Part 56, IRBs, and 21 CFR Part 50, Protection of Human Subjects). Ethical approval for the study was granted from Sterling Institutional Review Board, Sterling Independent Services, Inc., Atlanta, GA, USA. All subjects gave written informed consent to participate; in addition, written informed consent of a parent or legal guardian was obtained for participants aged 16 or 17 years. 2.2. Patients Subjects were recruited into the study through advertisement (radio, billboards, print, Internet), by referral from Sub-Investigators/community practitioners, via a search of Premier Research (Austin, TX, USA) database for eligible candidates and recommendation by previous study participants. Responders underwent preliminary telephone screening and those deemed suitable attended a screening visit at the investigational site. Only subjects meeting the following criteria were included in the study: aged at least 16 years; had at least 3 impacted third molars (2 of which had to be mandibular); experiencing moderate to severe postoperative pain based on the Pain Intensity (PI) Categorical Rating Scale and had a Pain Intensity Visual Analogue Scale (PI VAS) score of 50 mm or greater on the 100-mm VAS within 6 hours of completion of surgery, but more than 1.5 hours after the last administration of remifentanil. Candidates were excluded if they had current renal or hepatic disease, any ongoing painful condition that the investigator felt may have signicantly interfered with the subjects suitability,

or a recent (ie, within the previous year) or recurrent history of peptic ulcers, duodenal ulcers, or gastrointestinal bleeding. Concomitant medication was not permitted during the study. 2.3. Treatments Patients were randomised, according to a computer-generated system, to 1 of the following 5 treatment regimens: 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg (test treatment); 1 tablet of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg plus 1 placebo tablet (test treatment); 2 tablets of ibuprofen 200 mg/codeine 12.8 mg (Nurofen Plus, Reckitt Benckiser Healthcare International, Hull, UK [reference treatment]); 2 tablets of paracetamol 500 mg/codeine 15 mg (Panadeine Extra, GlaxoSmithKline Consumer Healthcare, Middlesex, UK [reference treatment]); or 2 placebo tablets. Subjects were stratied according to baseline pain severity and randomised using blocks of 12; each block consisted of 3 randomisation numbers for the 2 test treatments and the ibuprofen/codeine reference treatment, 2 numbers for the paracetamol/codeine reference treatment, and 1 number for placebo. Each treatment consisted of 2 white tablets of a similar size and was administered as a single oral dose taken with approximately 300 mL of water. Subjects were instructed to take the study medication after they rated their pain intensity as moderate or severe on the ordinal scale and at least 50 mm on the VAS. Rescue medication was available to subjects at any time post dosing, but they were encouraged to wait for at least 90 minutes after the rst dose of study medication. If rescue medication was needed within the rst 4 hours following administration of study medication, Ultram (tramadol 100 mg; Ortho-McNeil Janssen, Titusville, NJ) was given and if a second dose was required within this 4 hours, Toradol (ketorolac 30 mg intravenously/intramuscularly; Roche Pharmaceuticals, Nutely, NJ) was given; if rescue medication were needed after the rst 4 hours, Lortab (paracetamol/hydrocodone; UCB Pharma, Inc., Smyrna, GA) or tramadol were provided. All efcacy assessments were recorded by subjects in a pain assessment questionnaire under supervision of trained staff using a sequence of questions and procedures that were standardised across all sites. Pain assessments were conducted at 0.25, 0.5, 0.75, 1, 1.5, 2 hours, and hourly thereafter up to 12 hours post dose and just prior to rescue medication (if applicable). For PI (ordinal), the level of pain was rated on a 4-point ordinal rating scale (0 = No Pain, 1 = Mild Pain, 2 = Moderate Pain, 3 = Severe Pain) in response to the question What is your pain level at this time? PI (VAS) was rated on a horizontal 100-mm VAS labelled: No Pain (0 mm) as the left anchor and Worst Pain (100 mm) as the right anchor, in response to the instruction Please indicate with a line on the scale below your pain at this time. Pain relief (PR) was rated on a 5-point ordinal scale (0 = None, 1 = A little, 2 = Some, 3 = A lot; 4 = Complete) in response to the question How much relief have you had from your starting pain? Pain Half Gone was assessed (up to the point of an afrmative response) by the subject ticking either Yes or No on the pain assessment questionnaire in response to the question Is your starting pain at least half gone? Patient Global Assessment was performed at 12 hours or just prior to rescue medication, if sooner, assessed on a 5-point ordinal scale (1 = Poor, 2 = Fair, 3 = Good, 4 = Very Good, 5 = Excellent) in response to the question How effective do you think the study medication is as a treatment for pain? Safety assessments comprised vital signs, clinical laboratory tests (standard haematology, biochemistry and urinalysis; viral serology at screening), physical examination, pregnancy testing, medication and therapy history, adverse events (AE) from dosing until completion of the follow-up visit. AEs were recorded as mild, moderate, or severe, and the Investigator (or medically qualied

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Co-Investigator) determined their relationship as denitely, probably, possibly, unlikely, or not related to the study medication. 2.4. Endpoints The primary efcacy endpoint was the sum of the mean scores of PR combined with PI differences over 12 hours (SPRID 012 h, ie, the sum of the PI difference and the PR score integrated over the follow-up time period). Secondary endpoints included SPRID at 04 hours, 06 hours and 08 hours; Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) both at 04 hours, 0 6 hours, 08 hours, and 012 hours; time to pain half gone; patient global assessment; duration of effect (time to rst administration of rescue medication); peak pain relief during the 12-hour assessment period. Although many single dose dental pain studies contain an observation period of 68 hours, the observation period in this study was continued for 12 hours because this single-tablet combination of ibuprofen/paracetamol had previously been observed to offer sustained analgesia, suspected to be in excess of 68 hours [28], and this study sought to determine the full duration of efcacy. Safety endpoints included incidence of AEs, clinical laboratory tests and vital signs, medication and therapy history from 30 days before screening until completion of the follow-up visit. 2.5. Sample size and statistical methods It was calculated that 168 subjects were required in the respective treatment groups to detect a mean difference of 0.57 in SPRID 08 h between 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs ibuprofen 200 mg/codeine 12.8 mg, assuming 90% power, a 2-sided 5% signicance level, a 2-sample test, and a standard deviation of 1.6. This calculation was based on 8-hour data, as no suitable 12-hour data were available. However, it was expected that the difference between these treatments would be larger over 12 hours, so the study was adequately powered to meet its primary objective. It was calculated that based on previous experience, that is, assuming a 30% dropout rate during the screening phase and a 5% dropout rate during the randomised phase, approximately 1012 subjects would need to be screened and approximately 708 would need to be randomised and dosed in the study. However, the withdrawal rate after randomisation was lower than expected (1.3%) and 678 subjects were randomised and received study medication. The actual variability observed for the primary efcacy endpoint for the intention-to-treat (ITT) population was 1.61, and the observed difference between 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs ibuprofen/ codeine was 0.67; so the study was adequately powered to meet its objectives. The null hypothesis was the equality of the treatments being compared, and all statistical tests performed were 2-tailed with signicance determined by reference to the 5% signicance level; treatment comparisons are reported with 95% condence intervals for the difference. The primary method of analysis for SPRID 012 h was analysis of variance (ANOVA) assuming xed effects. The statistical model included factors for centre, gender, baseline pain, and treatment. All primary treatment comparisons were based on the estimates and standard errors from this model and were performed in a specied order according to a closed test procedure, which was to stop if the previous comparison was not statistically signicant at the 2sided 5% level. All secondary endpoints and the supportive analyses were considered as descriptive evidence of efcacy and were analysed without any procedures to account for multiple comparisons. Sec-

ondary endpoints based on PI and/or PR were analysed using either the same model as for the primary efcacy endpoint, or using analysis of covariance with the same factors as for the primary efcacy endpoint but with a covariate for baseline pain as measured on the VAS. Time-to-event endpoints were analysed using Coxs proportional hazards regression models with factors for centre, gender, baseline pain, and treatment to obtain an estimate of the hazard ratio and the associated 2-sided 95% condence interval. Ties were handled using Breslows method. Survival curves were produced using KaplanMeier estimates based on the raw data. Proportions were analysed using a logistic regression model with the same factors as above. All scheduled assessments completed after the subject had taken rescue medication or withdrawn were considered missing. For PR, PI, and pain half gone, missing values between 2 available assessments were linearly interpolated. Missing readings that could not be interpolated were replaced with the baseline PI, zero relief, or pain half gone equal to zero (ie, not reported). All the area-under-curve (AUC) analyses (SPRID, SPID, and TOTPAR) were based on the assumption that the baseline assessment took place at time zero, whilst actual timings were used for all other assessments to enable the inclusion of assessments taken at the time of rescue medication in the AUC calculation. All AUC (0X hours) values were calculated using the trapezoidal rule and were divided by X for ease of interpretation. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 12.1. Logistic regression models were tted with a single factor for treatment group comparing the proportion of subjects reporting a treatment emergent AE, a severe treatment emergent AE, and a treatment-related treatment emergent AE. From this model, odds ratios with corresponding 95% condence intervals were presented for the pairwise comparisons of interest. All subjects who took the dose of study medication were included in the analysis of safety. All subjects who were randomised to the study, took the study medication and completed the baseline efcacy assessment, and had at least one postbaseline assessment were included in the ITT population. All subjects who fullled the criteria for ITT in addition to completing pain assessment readings for at least 50% of the time points over the 12-h study period, and who did not take rescue medication within 90 minutes of the rst dose, were included in the per-protocol population. All data recorded for assessments performed subsequent to rescue medication were replaced by the subjects baseline score for pain intensity (Baseline Observation Carried Forward) and zero pain relief. All efcacy variables were analysed using the ITT population.

3. Results 3.1. Patients Between February 9 and September 17, 2009, 678 subjects were randomised into the study (Fig. 1). Subjects were recruited in 3 centres: Salt Lake City, UT (243 subjects randomised); San Marcos, TX (229 subjects randomised); and Austin, TX (206 subjects randomised). The majority of subjects were female (407 [60.0%]) and white (635 [93.7%]), with a mean age of 20.0 years. The treatment groups were balanced with respect to these and other baseline variables (Table 1). All subjects received local anaesthesia using 2% xylocaine with 1:100,000 epinephrine following intravenous sedation. A total of 236 (34.8%) subjects reported alcohol use prior to study enrolment, 159 (23.5%) were smokers or former smokers prior to study enrolment, and 126 (18.6%) subjects were former drug abusers or users.

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Excluded n=249

635

Assessed for eligibility N=959

Enrolment

Abnormal laboratory results n=27 Drug/alcohol abuse (previous 6 months) n=17 Impaction score <9 n=47 Inadequate birth control n=14 Taking prohibited medication n=5 Unsuitable medical history n=48 Inability to comply with protocol n=34 Withdrew consent n=43 Other n=14

Underwent surgery n=710 Randomized n=678

Did not receive dose n=32

Allocation

2 x single tablet combination of ibuprofen 200 mg/ paracetamol 500 mg

2 x single tablet combination of ibuprofen 200 mg/ paracetamol 500 mg

2 x ibuprofen 200 mg/ codeine 12.8 mg

2 x paracetamol 500 mg/ codeine 15 mg

2 x placebo

n=55

n=169

n=113

n=168

n=173

Follow-up

Withdrew n=4

Withdrew n=1

Withdrew n=2

Withdrew n=1

Withdrew n=1

Analysis

Analysed n=164

Analysed n=172

Analysed n=167

Analysed n=112

Analysed n=54

Fig. 1. CONSORT ow diagram showing assignment of subjects throughout the study.

In total, 46 (6.8%) subjects reported at least one major protocol deviation that resulted in some or all of their data being excluded from the per-protocol population. Twenty-ve (3.7%) subjects used rescue medication within 90 minutes of taking the study medication; 7 (4.0%) in the 1-tablet single-tablet combination of ibuprofen/paracetamol group, 3 (1.8%) in the ibuprofen/codeine group, 2 (1.8%) in the paracetamol/codeine group, and 13 (23.6%) in the placebo group. Other reasons for exclusion included use of ice packs, missing diary assessments, and vomiting following dosing with study medication. 3.2. Primary efcacy endpoint The primary efcacy endpoint, SPRID 012 h, was analysed using an ANOVA model with factors for baseline pain intensity (moderate or severe), treatment group, gender, and study centre. The results for the ITT population are summarised in Table 2 and

Fig. 2. The effects of treatment (P < 0.0001) and gender (P = 0.0055) were statistically signicant in the ANOVA model; neither baseline pain intensity nor study centre were signicant. Analysis of the primary endpoint demonstrated that 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg were statistically signicantly more efcacious than 2 tablets of placebo (P < 0.0001), paracetamol/codeine (P < 0.0001), and ibuprofen/codeine (P = 0.0001). Furthermore, 1 tablet of the singletablet combination of ibuprofen 200 mg/paracetamol 500 mg was statistically signicantly superior to 2 tablets of paracetamol/ codeine (P = 0.0001) and noninferior to 2 tablets of ibuprofen/ codeine. One tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was to be deemed noninferior to ibuprofen/codeine if the lower limit of the 95% condence interval for the mean difference between the 2 treatments was P 50% of the mean difference between ibuprofen/codeine and placebo. The mean difference between ibuprofen/codeine and placebo was

Table 1 Demographics of the intention-to-treat study population. One tablet of ibuprofen 200 mg/ paracetamol 500 mg (n = 173) Age, years, mean (SD) Gender, n (%) female Race, n (%) White Black Asian American Indian/Alaskan native Native Hawaiian/Pacic Islander Other Weight, kg, mean (SD) Height, cm, mean (SD) BMI, kg/m2, mean (SD) 20.2 (3.3) 105 (60.7) 165 (95.4) 4 (2.3) 3 (1.7) 0 1 (0.6) 0 68.1 (14.5) 168.5 (10.0) 24.0 (4.8) Two tablets of ibuprofen 200 mg/ paracetamol 500 mg (n = 168) 19.8 (3.2) 100 (59.5) 158 (94.0) 4 (2.4) 4 (2.4) 1 (0.6) 0 1 (0.6) 69.0 (15.2) 169.3 (10.1) 24.0 (4.3) Two tablets of ibuprofen 200 mg/ codeine 12.8 mg (n = 169) 20.1 (3.4) 101 (59.8) 154 (91.1) 2 (1.2) 7 (4.1) 2 (1.2) 1 (0.6) 3 (1.8) 68.8 (15.3) 169.5 (9.8) 23.9 (5.0) Two tablets of paracetamol 500 mg/ codeine 15 mg (n = 113) 19.7 (3.3) 68 (60.2) 107 (94.7) 3 (2.7) 1 (0.9) 0 1 (0.9) 1 (0.9) 70.8 (16.1) 168.5 (9.7) 24.9 (5.3) Placebo (n = 55)

19.8 (3.6) 33 (60.0) 51 (92.7) 2 (3.6) 2 (3.6) 0 0 0 71.0 (18.7) 168.7 (9.5) 25.0 (6.5)

BMI, body mass index; SD, standard deviation.

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Table 2 SPRID 012 h: the sum of the pain intensity difference and the pain relief score over the 12-hour follow-up period (ITT population). One tablet of ibuprofen 200 mg/ paracetamol 500 mg (n = 173) LS means (ANOVAb) Ranka 2.71 B Two tablets of ibuprofen 200 mg/ paracetamol 500 mg (n = 168) 3.33 A Estimate 2.76 1.36 0.67 0.75 0.06 2.15 0.61 0.68 2.09 1.40 Two tablets of ibuprofen 200 mg/ codeine 12.8 mg (n = 169) 2.65 B SE 0.25 0.2 0.18 0.2 0.17 0.25 0.17 0.2 0.25 0.27 Two tablets of paracetamol 500 mg/ codeine 15 mg (n = 113) 1.97 C 95% CI for estimate 2.27, 3.25 0.97, 1.74 0.33, 1.02 0.36, 1.13 -0.28, 0.40 1.66, 2.64 0.27, 0.95 0.30, 1.07 1.60, 2.58 0.88, 1.92 Placebo (n = 55)

0.56 D P-value <0.0001 <0.0001 0.0001 0.0001 0.72 <0.0001 0.0005 0.0005 <0.0001 <0.0001

Stepc pairwise comparisons (1) Two tablets of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs placebo (2) Two tablets of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets paracetamol 500 mg/codeine 15 mg (3) Two tablets of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets of ibuprofen 200 mg/codeine 12.8 mg (4) One tablet of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets of paracetamol 500 mg/codeine 15 mg (5) One tablet of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets of ibuprofen 200 mg/codeine 12.8 mg (-) One tablet of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs placebo (-) Two tablets of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 1 tablet of single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg (-) Two tablets of ibuprofen 200 mg/codeine 12.8 mg vs 2 tablets paracetamol 500 mg/ codeine 15 mg (-) Two tablets of ibuprofen 200 mg/codeine 12.8 mg vs placebo (-) Two tablets paracetamol 500 mg/codeine 15 mg vs placebo

SPRID, sum of the pain intensity difference and the pain relief; ITT, intention to treat; ANOVA, analysis of variance; CI, condence interval; LS, least squares; SE, standard error. a Letter A indicates the most effective treatment. Treatments with the same letter are not signicantly different from each other. b ANOVA model had factors for treatment (P < 0.0001), baseline Pain Intensity (ordinal) (P = 0.47), gender (P = 0.0055), and centre (P = 0.91). c Step of the multiple treatment comparison closed testing procedure.

2.09, thus, the lower limit of the condence interval for the mean difference between the 2 treatments had to be P 1.05. The lower limit of the 95% condence interval for the difference between 1 tablet of the ibuprofen/paracetamol combination tablet and 2 tablets of ibuprofen/codeine was 0.28, thus the noninferiority criterion was easily satised, although the difference between these 2 treatments was not statistically signicant (P = 0.72). The remaining 5 possible treatment comparisons were also carried out, although they were not part of the closed-test procedure. Two tablets of the single-tablet combination of ibuprofen 200 mg/

paracetamol 500 mg were statistically signicantly more efcacious than 1 tablet of the same single-tablet combination (P = 0.0005). Two tablets of ibuprofen/codeine were statistically signicantly more efcacious than 2 tablets of paracetamol/ codeine (P = 0.0005), and both these active codeine combinations, together with 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, were statistically signicantly more efcacious than placebo (P < 0.0001). These results illustrate a clear difference between the 5 study treatments. The results of all 5 planned primary comparisons were

5
2 x ibuprofen 200 mg/ paracetamol 500 mg 1 x ibuprofen 200 mg/ paracetamol 500 mg 2 x ibuprofen 200 mg/ codeine 12.8 mg 2 x paracetamol 500 mg/ codeine 15 mg placebo

Sum of the pain intensity difference and the pain relief score

0 0 1 2 3 4 5 6 7 8 9 10 11 12

Time (hours)
Fig. 2. Mean pain relief and intensity differences shown at each time point (intention-to-treat population).

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positive for both 1 and 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg compared with the other treatments. Moreover, with the exception of 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets of ibuprofen/codeine, the ibuprofen/paracetamol combination achieved statistical signicance in all of the 7 pairwise comparisons. The results of the per-protocol analysis were qualitatively identical to those of the ITT analysis. 3.3. Secondary efcacy endpoints The results for SPRID from 04, 06, and 08 hours were quantitatively similar to the primary endpoint (SPRID 012 h). In the pairwise comparisons, 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically signicantly more efcacious than all the other study treatments, in all 3 analyses, with the exception of SPRID 04 h for 1 tablet of the single-tablet combination of ibuprofen/paracetamol. One tablet of the single-tablet combination of ibuprofen/paracetamol was also statistically significantly more efcacious than 2 tablets of paracetamol/codeine in all 3 analyses. The results for SPID (ordinal), SPID (VAS), and TOTPAR at 04, 06, 08, and 012 hours are summarised in Table 3; and mirrored the results obtained for the equivalent SPRID analyses. All the pairwise comparisons for SPID (ordinal) 012 h, SPID (VAS) 012 h, and TOTPAR 012 h were statistically signicant, with the exception of 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs 2 tablets of ibuprofen/ codeine. The same pairwise comparisons were also statistically signicant at 06 and 08 hours. For SPID (ordinal) 04 h, SPID (VAS) 04 h, and TOTPAR 04 h, 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg were statistically superior to all treatments (P 6 0.007), with the exception of 1 tablet of the single-tablet combination of ibuprofen/paracetamol. In addition, 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was statistically better than 2 tablets of paracetamol/codeine (P 6 0.02). Furthermore, with respect to these variables, all treat-

ments were statistically signicantly more efcacious compared with placebo (P < 0.0001). The PR scores from 15 minutes to 12 hours post dose are shown in Fig. 3. With respect to the least square means estimated from the ANOVA models for each postbaseline assessment, peak pain relief occurred at 3 hours post dose for 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg and at 2 hours post dose for 1 tablet of the single-tablet combination of ibuprofen/paracetamol and 2 tablets of ibuprofen/codeine, and at 90 minutes post dose for paracetamol/codeine. One tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was statistically more efcacious than placebo up to 10 hours post dose and 2 tablets were statistically more efcacious at all timepoints. The reference combinations of ibuprofen/codeine and paracetamol/codeine were statistically more efcacious than placebo for up to 11 hours post dose and up to and including 7 hours post dose, respectively. The pain relief scores over time curves are shown in Fig. 3 and illustrate that the peak pain relief was higher and sustained for longer with 2 tablets of the singletablet combination of ibuprofen/paracetamol compared with all other treatments. The duration of pain relief was similar for 1 tablet of ibuprofen/paracetamol and ibuprofen/codeine but 2 tablets of ibuprofen/paracetamol produced consistently more pain relief. Similarly, in terms of pain intensity difference ordinal, 1 and 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg were statistically signicantly more efcacious than placebo for up to 9 hours post dose and at all timepoints, respectively. Furthermore, 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg provided signicantly more pain relief than 1 tablet from 5 hours onward (P 6 0.05). The reference combinations of ibuprofen/codeine and paracetamol/codeine were more efcacious, in terms of PI ordinal, from 30 minutes to 10 hours, inclusively, and up to and including 6 hours, respectively. The duration of effect of treatment was measured as the time to rst administration of rescue medication. The KaplanMeier estimates for median time to use of rescue medication were: 597 minutes for 2 tablets of the single-tablet combination of ibuprofen

Table 3 LS means for SPRID from 0 to 4, 6, and 8 hours and for SPID (ordinal), SPID (VAS), and TOTPAR from 0 to 4, 6, 8, and 12 hours post dose (ITT population). One tablet of ibuprofen 200 mg/ paracetamol 500 mg (n = 173) Ranka SPRID 04 h 06 h 08 h SPID (ordinal) 04 h 06 h 08 h 012 h SPID (VAS) 04 h 06 h 08 h 012 h TOTPAR 04 h 06 h 08 h 012 h 3.64 A, B 3.66 B 3.40 B 1.30 1.30 1.20 0.94 42.5 43.3 40.3 31.9 2.34 2.36 2.21 1.77 A, B B B B A, B B B B A, B B B B Two tablets of ibuprofen 200 mg/ paracetamol 500 mg (n = 168) Ranka 3.93 A 4.06 A 3.92 A 1.43 1.47 1.41 1.17 46.9 48.9 47.1 39.7 2.50 2.58 2.51 2.16 A A A A A A A A A A A A Two tablets of ibuprofen 200 mg/ codeine 12.8 mg (n = 169) Ranka 3.44 B, C 3.46 B 3.24 B 1.23 1.23 1.14 0.92 39.3 40.3 37.8 30.8 2.22 2.23 2.10 1.73 B, C B B B B, C B B B B, C B B B Two tablets of paracetamol 500 mg/ codeine 15 mg (n = 113) Ranka 3.18 C 2.87 C 2.50 C 1.11 1.00 0.86 0.67 36.3 32.9 28.7 22.8 2.07 1.87 1.64 1.30 C C C C C C C C C C C C Placebo (n = 55) Ranka

0.57 D 0.58 D 0.57 D 0.12 0.14 0.15 0.17 4.8 6.0 6.3 6.5 D D D D

D D D D D D D D

0.44 0.44 0.42 0.40

SPID, sum of pain intensity differences; SPRID, sum of the pain intensity difference and the pain relief score; TOTPAR, sum of total pain relief; VAS, visual analogue scale. a Letter A indicates the most effective treatment; treatments with the same letter are not signicantly different from each other.

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200 mg/paracetamol 500 mg, 491 minutes for 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, 483 minutes for 2 tablets of ibuprofen/codeine, 347 minutes for 2 tablets of paracetamol/codeine, and 101 minutes for placebo. The KaplanMeier survival curves for the time to rst administration of rescue medication are shown in Fig. 4. In terms of the proportion of subjects requiring rescue medication, fewer subjects taking 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg required rescue medication compared to the other 4 treatments (P < 0.04); the proportion of subjects taking 2 tablets of ibuprofen/paracetamol who did not use rescue medication over the 12-hour study period was 33.3%. Ibuprofen/codeine was also statistically signicantly superior to placebo in this respect, while none of the other comparisons were statistically signicant. The KaplanMeier estimates for median time to unconrmed perceptible pain relief were 16.9 minutes and 19.8 minutes for 1 and 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, respectively, and 18.4, 22.3, and 113.6 minutes for paracetamol/codeine, ibuprofen/codeine, and placebo, respectively. All the pairwise comparisons of active treatments vs placebo were statistically signicant (P < 0.0001), as was 2 tablets of the single-tablet combination of ibuprofen/paracetamol compared with 1 tablet and ibuprofen/codeine (P < 0.04); none of the other pairwise comparisons reached statistical signicance. The KaplanMeier estimates for median time to pain half gone were 30 minutes for 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, 44 minutes for 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, 45 minutes for 2 tablets of both ibuprofen/codeine and paracetamol/codeine, and 300 minutes for placebo. In terms of the proportion of subjects reporting pain half gone, all treatment groups were statistically signicantly more efcacious compared with placebo (P < 0.0001), and 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was signicantly superior to both 2 tablets of ibuprofen/codeine and paracetamol/ codeine (P < 0.03). None of the other pairwise comparisons reached statistical signicance. A summary of subjects overall assessment of study medication assessed at 12 hours or just prior to administration of rescue medication, if applicable, is shown in Fig. 5. A total of 39/165 (23.6%)

subjects considered 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg to be excellent, compared with 23/169 (13.6%) subjects who took 1 tablet of this combination and 26/167 (15.6%) of subjects who took 2 tablets of ibuprofen/ codeine, 7/113 (6.2%) of subjects who took 2 tablets of paracetamol/codeine and 1 (1.8%) subject who took placebo. In the ANOVA model, the effect of treatment group was highly statistically significant (P < 0.0001), while the effect of baseline pain, gender, and pain were not statistically signicant. The least square means scores for each treatment were: 3.70 for 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, 3.45 for 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, 3.40 for 2 tablets of ibuprofen/codeine, 3.06 for 2 tablets of paracetamol/codeine, and 1.44 for placebo. Two tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was statistically signicantly better than all other treatments (P < 0.033). With the exception of 1 tablet of the singletablet combination of ibuprofen 200 mg/paracetamol 500 mg vs ibuprofen/codeine, all other pairwise comparisons were statistically signicant. 3.4. Safety and tolerability During the course of the study there were no serious AEs, and no subject withdrew due to an AE. AEs recorded during the study, including the follow-up period, are summarised in Table 4. During the study, 6 AEs occurred in at least 5% of subjects in at least 1 of the 5 treatment groups. These 6 AEs, in order of overall incidence, were nausea (26.7%), vomiting (19.5%), headache (14.9%), dizziness (9.9%), alveolar osteitis (3.7%), and body temperature increased (2.7%). Treatment emergent AEs were dened as those AEs that occurred within 12 hours of taking study medication. The prevalence of treatment emergent AEs was much lower in the group taking either 1 or 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg (24.9% and 18.5% of subjects, respectively) compared with the groups taking 2 tablets of either ibuprofen/codeine (34.9%) or paracetamol/codeine (39.8%) or placebo (38.2%). The pairwise comparisons between 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg

3.0
2 x ibuprofen 200 mg/ paracetamol 500 mg 1 x ibuprofen 200 mg/ paracetamol 500 mg 2 x ibuprofen 200 mg/ codeine 12.8 mg 2 x paracetamol 500 mg/ codeine 15 mg placebo

2.5

2.0 Pain relief score

1.5

1.0

0.5

0.0 0 1 2 3 4 5 6 7 Time (hours) 8 9 10 11 12

Fig. 3. Mean pain relief at each time point (intention-to-treat population).

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2 x ibuprofen 200 mg/ paracetamol 500 mg 1 x ibuprofen 200 mg/ paracetamol 500 mg 2 x ibuprofen 200 mg/ codeine 12.8 mg 2 x paracetamol 500 mg/ codeine 15 mg placebo

100 Percentage of subjects that had used rescue medication 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Time (hours) 7 8

10

11

12

Fig. 4. KaplanMeier plot for time to rst administration of rescue medication (intention-to-treat population).

vs placebo (P = 0.0033), 2 tablets of paracetamol/codeine (P = 0.0001), and 2 tablets of ibuprofen/codeine (P = 0.0008) were all statistically signicant. Similarly, the rates of reporting in the group taking 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg vs paracetamol/codeine (P = 0.008) and ibuprofen/codeine (P = 0.04) were both statistically signicant. The prevalence of severe treatment emergent AEs was 1.2% of subjects in both groups taking the single-tablet combination ibuprofen/paracetamol, 3.6% of subjects in the ibuprofen/codeine group, 8.0% of subjects in the paracetamol/codeine group, and 5.5% of subjects in the placebo group. The pairwise comparisons between both the single-tablet combination of ibuprofen/paracetamol groups and paracetamol/codeine were statistically signicant (P = 0.012 and P = 0.013 for 1 tablet and 2 tablets, respectively). Treatment-related AEs were dened as those that were denitely, probably, or possibly related to the study medication. The rates of reporting such events in the 2 ibuprofen/paracetamol combination groups were 4.8% in the group taking 2 tablets and 5.8% in the group taking 1 tablet. The reported rates of treatment-related AEs for the other groups were 16.6% (ibuprofen/codeine), 16.8% (paracetamol/codeine), and 16.4% (placebo). The pairwise compar-

isons in terms of rates of reporting of treatment-related AEs for 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg were statistically signicant in favour of this combination, vs placebo (P = 0.008), ibuprofen/codeine (P = 0.0009), and paracetamol/codeine (P = 0.002). Similarly, for 1 tablet of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg, the rates of reporting were statistically signicant in favour of this combination, vs ibuprofen/codeine (P = 0.002) and paracetamol/codeine (P = 0.004). 4. Discussion This study compared the efcacy and tolerability of a novel single-tablet combination of ibuprofen 200 mg and paracetamol 500 mg with that of the analgesic combinations ibuprofen/codeine and paracetamol/codeine, which are currently available without prescription in many parts of the world. All active treatments were statistically signicantly superior to placebo. The ranking of the 5 treatments in terms of the primary efcacy endpoint, from best to worst, was: 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg; 1 tablet of the single-tablet

Poor, Fair
89.1%

Good, Very Good, Excellent

10.9% Placebo

27.4%

72.6%

2 x paracetamol 500 mg/ codeine 15 mg 2 x ibuprofen 200 mg/ codeine 12.8 mg 1 x ibuprofen 200 mg/ paracetamol 500 mg

22.2%

77.9%

18.4%

81.6%

15.2%

84.8%

2 x ibuprofen 200 mg/ paracetamol 500 mg

Poor

Fair

Good

Very Good

Excellent

Fig. 5. First recorded postbaseline assessment of subjects overall assessment of study medication (intention-to-treat population).

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Table 4 Severity of adverse events (AE) and most common (>5% of subjects in any treatment group) adverse events reported during the whole study period (safety population). One tablet of ibuprofen 200 mg/ paracetamol 500 mg (n = 173) Any AE, n (%) of subjects Treatment emergent AE (within 12 h of dosing) Severity, n (%) of subjects Mild Moderate Severe 88 (50.9) 43 (24.9) 49 (28.3) 48 (27.7) 7 (4.0) Two tablets of ibuprofen 200 mg/ paracetamol 500 mg (n = 168) 87 (51.8) 31 (18.5) 54 (32.1) 40 (23.8) 9 (5.4) Two tablets of ibuprofen 200 mg/ codeine 12.8 mg (n = 169) 97 (57.4) 59 (34.9) 68 (40.2) 48 (28.4) 13 (7.7) Two tablets of paracetamol 500 mg/ codeine 15 mg (n = 113) 72 (63.7) 45 (39.8) 42 (37.2) 35 (31.0) 14 (12.4) Placebo (n = 55)

35 (63.6) 21 (38.2) 21 (38.2) 16 (29.1) 4 (7.3)

Primary system organ class preferred term, n (%) of subjects Gastrointestinal disorders Nausea Vomiting Infections and infestations Alveolar osteitis Investigations Body temperature increased Nervous system disorders Dizziness Headache 43 (24.9) 29 (16.8) 8 (4.6) 2 (1.2) 12 (6.9) 19 (11.0) 33 (19.6) 30 (17.9) 4 (2.4) 3 (1.8) 15 (8.9) 19 (11.3) 50 (29.6) 35 (20.7) 9 (5.3) 9 (5.3) 23 (13.6) 32 (18.9) 37 (32.7) 25 (22.1) 3 (2.7) 3 (2.7) 14 (12.4) 21 (18.6) 18 (32.7) 13 (23.6) 1 (1.8) 1 (1.8) 3 (5.5) 10 (18.2)

combination of ibuprofen 200 mg/paracetamol 500 mg and 2 tablets of ibuprofen 200 mg/codeine 12.8 mg (Nurofen Plus); 2 tablets of paracetamol 500 mg/codeine 15 mg (Panadeine Extra); placebo. This study showed that 1 or 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was statistically signicantly more efcacious than 2 tablets of paracetamol/ codeine in terms of the primary endpoint, SPRID 012 h. In addition, 1 or 2 tablets of the single-tablet combination of ibuprofen/ paracetamol were found to be noninferior and superior, respectively, to 2 tablets of ibuprofen/codeine and 2 tablets of paracetamol/codeine. The peak pain relief was both higher and sustained for longer with 2 tablets of the single-tablet combination of ibuprofen/paracetamol compared with all other treatments. The results for the secondary efcacy endpoints were quantitatively very similar to the primary endpoint and maintained the same ranking and clear separation of treatment efcacy. Less distinction was observed between treatments at the 04 hour time point, with the difference between 2 and 1 tablets of the singletablet combination of ibuprofen 200 mg/paracetamol 500 mg failing to reach statistical signicance. However, both doses of the single-tablet combination of ibuprofen/paracetamol were observed to be statistically superior to 2 tablets of paracetamol/codeine, during the 04 hour time frame. Adverse events were uncommon during the study; the events that occurred were minor and resolved without the need for intervention. No safety issues were raised. The proportion of subjects reporting treatment emergent AEs was statistically signicantly less with either 1 or 2 tablets of the single-tablet combination of ibuprofen/paracetamol compared with the codeine analgesic combinations. In previous dental pain studies, ibuprofen/paracetamol combinations have been associated with fewer AEs than placebo, particularly for nausea and vomiting, which are common postoperative side effects. Codeine is known to be associated with a number of side effects, including nausea and vomiting [8]. This single-tablet combination of ibuprofen/paracetamol is an effective, safe alternative for patients who are poor metabolisers of codeine or those who prefer not to take codeine due to its associated side effects (drowsiness, constipation, respiratory depression, emesis, urinary retention). NSAIDs, commonly ibuprofen, are widely prescribed for the relief of dental pain and provide good pain relief in this situation due to their combined antiinammatory and analgesic action. Paracetamol

is also used and is an effective analgesic but it does not have antiinammatory action. Opioids, most commonly codeine, are another type of analgesic used for dental pain but they are associated with signicant side effects and therefore often reserved for severe pain only [19]. Codeine is known to confer additional efcacy when used in combination with both ibuprofen and paracetamol, and there is conclusive evidence that codeine can boost the analgesic efcacy of paracetamol [14,17,37]. The evidence is less conclusive for a similar effect for codeine and ibuprofen [9,11,15,18,22,23,31,32,34,41], although a meta-analysis of published trials estimated that codeine 60 mg enhances the analgesic effect of ibuprofen 400 mg by approximately 8% [33]. A qualitative review of NSAIDs and paracetamol for postoperative pain found there were limited data on their combined use, but what studies there were had found that the combination of these 2 analgesics offered enhanced pain relief [21]. The rationale for combined analgesia is that enhanced pain relief can potentially be achieved using a lower dose and with reduced side effects [10]. A previous pilot study of concurrent administration of ibuprofen and paracetamol for acute postoperative dental pain found it offered superior analgesic efcacy compared with ibuprofen or paracetamol alone [26]. In the present study, 1 tablet of the novel single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg was found to be superior, with fewer side effects, to 2 tablets of paracetamol 500 mg/codeine 15 mg, and noninferior to 2 tablets of ibuprofen 200 mg/codeine 12.8 mg. Furthermore, 2 tablets of this single-tablet combination of ibuprofen/ paracetamol were superior to both codeine combinations. Therefore, this novel single-tablet combination of ibuprofen/paracetamol fulls the objectives of combination analgesia by offering reduced side effects with enhanced or equivalent efcacy from a lower dose of the individual components. The data also show that increasing the dose to 2 tablets of the single-tablet combination of ibuprofen/paracetamol offers superior pain relief compared with both the ibuprofen/codeine and paracetamol/codeine combinations. A limitation of this study is that the study population largely consisted of young adults, with an average age of 20 years. The dental pain model was utilised to assess the efcacy of pain relief. This is a widely accepted method, with a proven record of assay sensitivity in being able to distinguish active treatments from each other and placebo [6,10,12,24,25,28]. Furthermore, results from dental pain studies have been widely extrapolated to other general pain conditions, including the most common nonprescription conditions. This study was conducted using subjects who had undergone removal of

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a minimum of 3 bony impacted third molars in order to ensure that there was sufcient model sensitivity to demonstrate additional pain relief with the ibuprofen/paracetamol combination over the comparator ibuprofen/codeine combination, which is a strong nonprescription analgesic. Therefore, the young average age of participants was unavoidable due to the predominance of the need for impacted third molar extraction procedures in this age group. It is likely that the results would be similar in older adults. It could be argued that the primary endpoint of SPRID 012 h used in this study was too long, given that the proposed dosing recommendation is likely to be 1 or 2 tablets of the single-tablet combination of ibuprofen/paracetamol every 68 hours. However, the fact that the comparison of 2 tablets vs 1 tablet achieved statistical signicance at 5 hours suggests that greater analgesia would still be afforded by 2 tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg as the proposed dosing regimen. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics marketed for strong pain. Paracetamol combined with ibuprofen, at the dose range studied, is a more effective analgesic than codeine combined with ibuprofen. The novel single-tablet combination of ibuprofen/paracetamol would provide a useful alternative analgesic option for people not wishing to take codeine. 5. Conicts of interest statement Michael Goulder has no conict of interest to declare. Stephen Daniels served as an investigator and was an employee of Premier Research International whose clinics participated in this study. Sue Aspley is currently an employee, and Sandie Reader was previously an employee, of Reckitt Benckiser Healthcare International Ltd. The trial is registered at clinicaltrials.gov: NCT01229449. Acknowledgements

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[12]

[13]

[14] [15]

[16]

[17]

[18]

[19] [20] [21]

[22]

[23]

[24]

The authors would like to acknowledge the following for their valuable contributions to this study: The Premier Research Clinical Research Center staff in Austin, TX, San Marcos, TX, and Salt Lake City, UT; and the surgeons and sub-investigators who participated, Donald P. Bandy, DDS, David M. Anderson, DDS, MD, Kyle Christensen, DDS, Franklin S. Bonasso, DDS, R. Jasper Dean, DDS, and Mark Hutchens, MD. Editorial assistance for the development of this manuscript was provided by Debra Scates of Elements Communications, supported by Reckitt Benckiser Healthcare Ltd. This study was sponsored by Reckitt Benckiser Healthcare UK Ltd, Dansom Lane, Hull, HU8 7DS. References
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