Onset of Action and Efficacy of Ibuprofen Liquigel as Compared to Solid Tablets: A Systematic Review and Meta-Analysis

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1 Onset of Action nd Efficcy of Ibuprofen Liquigel s Compred to Solid Tblets: A Systemtic Review nd Met-Anlysis Hnn Al Lwti nd Fkhreddin Jmli Fculty of Phrmcy & Phrmceuticl Sciences, University of Albert, Edmonton, Albert, Cnd. Received, April 18, 2016; Revised August 2, 2016; Accepted, August 15, 2016; Published, August 16, ABSTRACT. Purpose. Ibuprofen liquigel hs been believed to provide fster nlgesic effect. However, comprtive studies evluting the efficcy of liquigel versus regulr tblets re not vilble. Hence, we crried out systemtic review nd met-nlysis to compre the onset of ction nd efficcy of over-the-counter doses of ibuprofen liquigel ( ) vs ibuprofen tblets (IBU T ). Methods. Published clinicl trils of nd IBU T were identified through systemtic serch of vrious dt bses up to October, Results. In totl 18 eligible studies on IBU T nd 4 on were found. There ws no significnt difference in the medin time to the first perceptible pin relief or the proportion of ptients with more thn % pin relief between the two products. However, yielded significntly greter odd rtios in meningful pin relief t 60, 90 nd 120 min, but not t 30 min, s compred with IBU T. Conclusion. The vilble evidence, lthough not overwhelming, suggest fster onset of nlgesi for liquigel s compred with tblets. This rticle is open to POST-PUBLICATION REVIEW. Registered reders (see For Reders ) my comment by clicking on ABSTRACT on the issue s contents pge. INTRODUCTION Ibuprofen is non-steroidl nti-inflmmtory drug (NSAID) derivtive of the propionic cid tht is used throughout the world for relief of pin nd inflmmtion in both cute nd chronic conditions [1]. The fvorble nlgesic effect of ibuprofen, even t low over-the-counter (OTC) orl doses, hs mde this gent the gold stndrd ginst which mny new gents re evluted for efficcy [2]. The mngement of cute episodes of pin requires the use of nlgesic gents tht hve the bility to get bsorbed rpidly nd efficiently to yield rpid onset of pin relief. Ibuprofen is Biophrmceutics Clssifiction System (BCS) ([3]) clss II drug with low solubility t ph 1.2 nd 4.5 but high solubility t ph 6.8, nd is very permeble through physiologicl membrnes [4]. In fct, it is found to be completely bsorbed llowing for lmost totl biovilbility. However, the onset of bsorption gretly depends on the dissolution of the dosge form [5]. In recent yers, vrious orl formultions nd different slts of ibuprofen hve been investigted for their bsorption properties nd for their speed of onset of ction with the hope of providing rpid rise in plsm concentrtions nd, hence, fst nlgesic effect. They include S(+) ibuprofen [6], ibuprofen lysine [7, 8], ibuprofen sodium [9], ibuprofen rginte [7, 10], nd ibuprofen liquigel (Advil Liqui-Gels, Pfizer, NY, USA). Ibuprofen liquigel is soft geltin cpsule tht is hermeticlly seled nd contins ibuprofen s free cid nd potssium slt in solubilised form [11]. This newer solid dosge form of ibuprofen hs been reported to hve rpid rte of bsorption in helthy volunteers [12]. While ibuprofen rte of bsorption in ptients in pin is not reported, it hs been shown to be n effective nlgesic with minor dvntges in onset of ction s compred with ketoprofen nd cetminophen 1000 mg [13, 14]. However, results of clinicl trils, if ny, tht compre liquigel with solid dosge forms of ibuprofen s n ctive comprtor hve not been reported, hence, ny dvntge of such formultions remins unproven. This is prticulrly importnt since, due to the populrity of ibuprofen liquigel, mny other nlgesics hve become vilble on the mrket in the form of liquid gel. We, therefore, ttempted to compre the onset of nlgesi nd efficcy of the liquigel with solid dosge forms of ibuprofen by Corresponding Author: Fkhreddin Jmli, Fculty of Phrmcy & Phrmceuticl Sciences, Ktz Centre for Phrmcy & Helth Reserch, Avenue, Edmonton, Albert, Cnd T6G 2E1. 301

2 undertking systemtic review nd met-nlysis of ll the studies tht report onset of nlgesi nd efficcy of ibuprofen fter dministrtion of these formultions for the tretment of dentl pin or migrine or tension-type hedche. METHOD Published reports of rndomized controlled trils on ibuprofen tblets (IBU T ) or liquigels ( ) t ny dose were identified through systemtic serch of PubMed, Embse, Google Scholr nd the Cochrne librry from inception until October, Key words used in the serch included: ibuprofen, onset, humn, dentl, orl surgery, migrine, nd tensiontype hedche. Moreover, the reference lists of the retrieved rticles were scnned for relevnt studies. The screening nd eligibility ssessment of the reports ws crried out independently by the two uthors. There ws lck of ccess to unpublished dt, nd so the review only included published reports. Moreover, conference bstrcts, cse reports, or clinicl observtions were found to lck the detils required in the nlysis, nd thus were not included. No lnguge restriction ws imposed. The review ws restricted to clinicl studies relted to the use of ibuprofen s n nlgesic for dentl pin, tension-type hedche, nd migrine. Studies were included if they were rndomized, double blind, nd plcebo controlled studies tht evluted single dose of ibuprofen dministered following moderte to severe episode of pin ssocited with one of the bove mentioned conditions. Multiple dose studies were included only if the relevnt single-dose dt were provided. Studies on the use of ibuprofen s pre-emptive tretment were not included, nor were studies which only used other thn the conventionl mrketed IBU T or. Therefore, ibuprofen slt formultions mrketed such s ibuprofen sodium or ibuprofen rginte were excluded from the review. The inclusion criteri lso required the use of the double stopwtch method, ptient popultion ged t lest 12 yers, nd monitoring the ptients for three hours or more post-dose. Relevnt studies were ctegorised on the bsis of whether the ibuprofen solid tblets or the ibuprofen liquigel were used. In instnces where the results from the studies where only reported grphiclly, the relevnt grphs were digitized using digitizeit ( Germny) nd the grbit function in MATLAB (MthWorks Inc., Ntick MA, USA), nd the dt were extrcted. In prticulr, the Kpln-Meier time to event curves were nlysed by the pproch suggested by Guyot et l [15]. Two mesures of onset of pin relief were considered, nmely, the time to the first perceptible pin relief (FPPR) nd the meningful pin relief (MPR), both of which re ptient-reported outcome cptured s prt of the double stopwtch method [16]. Kpln-Meier survivl medin times to the bove events were verged with the weights being proportionl to both the smple sizes nd inverse of the vrince. The ltter, however, ws mesurble only for the dt reported in the studies tht provided mesure of vrince. Moreover, the outcome of chieving meningful pin relief t 30, 60, 90, nd 120 min post-dose were clculted. The proportion of ptients chieving MPR t the bove specific times, nd the relevnt odd rtios (OR) ginst plcebo were clculted. Setting IBU T s the reference (OR=1), the OR for ws lso clculted by n djusted indirect comprison [17]. Vrition mong studies ws nticipted, nd due to the heterogeneity of the pooled dt the OR vlues for meningful pin relief were estimted using the DerSimonil-Lird method [18]. Heterogeneity mong the studies in reporting n outcome is detected using the Cochrn-Q test nd the percentge of vrition cross the different studies tht is ttributed to heterogeneity is quntified using the I 2 inconsistency test. As the mesure of efficcy, we clculted the totl pin relief score (TOTPAR) over 6 h. Pin relief is mesured throughout the study t specific time intervls on 5-point ctegoricl scle (0 (no relief), 1 (slight relief), 2 (moderte relief), 3 (good relief), 4 (complete relief)). TOTPAR, which is n integrted pin score representing time-weighted mesure of the totl re under the pin relief curve, hs higher sensitivity thn mny other outcome mesures such s the sum of pin intensity difference score [19]. We used the Student s t-distribution test to compre the clculted TOTPAR scores [20]. Moreover, we used verified liner regression equtions to clculte the proportion of ptients experiencing more thn % pin relief s mesured by TOTPAR, nd clculted the relevnt ORs ginst plcebo nd ginst ech other [21]. RESULTS The dtbse serch (Figure 1) resulted in 100 reports tht evluted ibuprofen tretment for dentl 302

3 pin or dentl surgery, migrine, or hedche, nd 3 dditionl reports were identified from other resources. Upon our preliminry screening, duplicte reports, only bstrcts, cse studies, reviews nd observtionl studies were removed. Subsequently, the list ws shortened to 64 reports. A further screening reveled tht 12 of these reports did not use rndomly controlled trils, nd 10 did not include ibuprofen s n ctive comprtor in the study; e.g., s rescue mediction. The remining 42 full text rticles were checked for eligibility. Among these, 4 studies were relted to the use of ibuprofen s preemptive tretment, 2 used ibuprofen lysine, 1 used extended-relese ibuprofen, 1 used sodium ibuprofen nd ibuprofen cid incorporting poloxmer, 8 did not include results of the double stopwtch method, 3 were not plcebo-controlled studies, nd 1 did not report plcebo results. The remining 22 studies (Tble 1) met our inclusion criteri nd were included in the review. These consisted of 18 studies tht used IBU T nd 4 tht studied. Among the IBU T studies, 4 used Motrin IB (Motrin, McNeil Consumer Helthcre, Fort Wshington PA, USA) (IBU Mot ), one used Advil (Pfizer Consumer Helthcre, New York NY, USA), one hd n rm for ech of these two brnds, one used Neurofen (Reckitt Benckiser, Slough, UK), while the rest either used unbrnded ibuprofen tblets or did not specify the brnd used. Identifiction 100 records identified through dtbse serching. 3 dditionl records dded. Screening 64 totl records fter removing duplictes nd preliminry screening for bstrcts, review ppers, nd cse studies. 64 records screened. 22 excluded: not rndomly controlled trils or ibuprofen not n ctive rm. Eligibility Included 42 full text rticles ssessed for eligibility. 22 studies included. 20 excluded: 4, preemptive tretment, 4, plcebo dt not given, 4, using other form of ibuprofen, 8, not using stopwtch method. 18 studies included for ibuprofen tblets (IBU T ): 5 used Motrin IB (IBU Mot ), 3 used other brnds, & the others didn t specify brnd used 4 studies included for ibuprofen liquigels ( ) Figure 1. Flow of informtion in the systemtic review 303

4 Tble 1. Ibuprofen studies included in the nlysis Reference Design Condition Number of ptients Reference Design Condition Number of ptients [30] DB, P, [14] DB, P, MD [13] DB, P, IBULG (Advil) Celecoxib 200 mg IBULG (Advil) Ketoprofen 25mg APAP [31] DB, P, Tensiontype hedche IBULG APAP IBULG (Advil) IBU liquigel 200 mg, APAP Reference Design Condition Number of ptients Reference Design Condition Number of ptients [34] DB, P, [35] DB, P, [37] DP, P, [39] DB, P, [10] DB, P, [40] DB, P, [42] DB, P, [43] DB, P, [46] DB, P, [48] DB, P, Tensiontype hedche Migrine (Motrin) 200 mg IBU rginte 200mg IBU rginte 400mg (Motrin) (Advil) IBU Sodium Celecoxib 200mg (Motrin) 200mg IBU rginte 200mg IBU rginte 400mg + Cffeine Cffeine (Advil) S(+) IBU 200mg S(+) IBU 400mg ASA 2 mg + cffeine 65 mg+ APAP 2 mg Pregblin mg Pregblin 300 mg Tpentdol 25mg Tpentdol mg Tpentdol 75mg Tpentdol 100mg Tpentdol 200mg Morphine sulphte 60mg [36] DB, P, [38] DB, P, [7] DB, P, [41] DB, P, [44] DB, P, [45] DB, P, [47] DB, P, [49] DB, P, Tensiontype hedche IBU: ibuprofen (dose is 400 mg if not specified), APAP: cetminophen (dose is 1000 mg if not specified), ASA: spirin DB: double blind, P: plcebo controlled, : single dose, MD: multiple dose. (Nurofen) IBU Effervescent 400mg Rofecoxib mg Celecoxib 200mg, 200 mg + cffeine mg + cffeine 100mg + cffeine 200mg (Motrin) 200mg IBU rginte 200mg IBU rginte 400mg APAP 1000 mg 200mg + APAP + APAP Rofecoxib mg (Motrin) IBU sodium 400 mg MK mg MK 0703 mg MK mg Lumircoxib 400mg Lumircoxib 100mg

5 Confirmed first perceptible pin relief All of the studies included in the review mesured pin relief over vrious times up to 12 h. Moreover, ll of the studies climed to hve used the double stopwtch method [16] but some did not report the dt. As mesure of onset of ction, FPPR hs been presented in 2 studies for nd in 16 studies for IBU T (Tble 2). Moreover, both of the studies nd five of the IBU T studies provided 95% confidence intervl for the medin times. FPPR ws chieved for % of ptients significntly fster following both IBU T nd s compred with plcebo. However, the difference between the two formultions ws not significnt. Confirmed meningful pin relief The MPR vlues were reported in ll 4 of the studies nd in 13 studies for IBU T (Tble 3). Moreover, ll of the studies nd 3 of the IBU T studies provided 95% confidence intervls for the medin times. As depicted in Tble 3, % of the ptients who used either IBU T or recorded significntly fster MPR thn those who took plcebo. The medin MPR ws significntly shorter for thn for IBU T. A gret del of vribility is observed with the IBU T studies with medin MPR rnging from 35 to 161 min. Moreover, when the nlysis is restricted to IBU Mot studies, the pooled medin time from 5 studies which reported the outcome reduces from 138 to 52 min with smple-size weighing. Another outcome mesure considered, which complements the medin times to MPR, is the proportion of ptients chieving MPR t 30, 60, 90, nd 120 min post-dose (Tble 4). Three rticles provided such dt nd so did 4 of the IBU T reports. One dditionl IBU T study provided the dt t ll times except t 90 min post-dose, nd one more provided the dt t only 60, nd 120 min post-dose. Both tretments provided significntly greter OR thn plcebo t ll mesured times. Tble 2. Medin times to the first perceptible pin relief (FPPR) for ibuprofen liquigel ( ) nd tblet (IBU T ) 400 mg IBU T 400 mg Reference Medin time, min (95% CI) Medin time, min (95% CI) Reference Medin time, min (95% CI) Medin time, min (95% CI) [14] 39.0 ( ) [39] c 24.0 ( ) 38.0 [31] 10.2 ( ) >180 [46] c 16.0 ( ) > 180 [35] c 30.6 ( ) 24.6 [36] c 24.0 ( ) > 180 Pooled (weighted by smple size) [49] c 41.5 ( ) > ( ) [34] d Pooled (inverse vrince) [37] b,d 25.8, 25.1 > ( ) [10] d [40] [48] 48.0 > 180 [38] [7] d [41] [44] 48.0 >180 [45] d 43.6 > 180 [47] 60.0 >180 Pooled (weighted by smple size) IBU T 32.5 IBU c T 26.9 ( ) d IBU MOT 22.6 Pooled (inverse vrince) c IBU T 22.4 ( ) 95% confidence intervl when vilble; b study hd two rms of ibuprofen; c studies tht reported 95% CI; d Motrin IB ws used in the study. 305

6 Reference Tble 3. Medin times to meningful pin relief (MPR) for ibuprofen liquigel ( ) nd tblet (IBU T ) 400 mg Medin time, min (95% CI) Medin time, min (95% CI) Reference IBU T 400 mg Medin time, min (95% CI) Medin time, min (95% CI) [30] 46.3 ( ) > 180 [39] c 61.0 ( ) > 180 [13] 24.2 ( ) > 180 [43] c 148 ( ) > 180 [14] 39.0 ( ) > 180 [35] c 47.4 ( ) > 180 [31] 28.8 ( ) > 180 [34] d 44.0 > 180 [37] b,d 60.7, 52.0 > 180 [10] d 48.0 > 180 Pooled (weighted by smple size) [40] 161 > ( ) [42] 35.0 > 180 Pooled (inverse vrince) [48] 48.0 > ( ) [38] 52.0 > 180 [41] 124 > 180 [7] d 58.0 > 180 [45] d 48.5 > 180 Pooled (weighted by smple size) IBU T 104 IBU c T 138 ( ) d IBU MOT 52.0 Pooled (inverse vrince) c IBU T 65.4 ( ) 95% confidence intervl when vilble; b study hd two rms of ibuprofen; c studies tht reported 95% CI; d Motrin IB ws used in the study. Tble 4. Odd rtio nd heterogeneity for the outcome of chieving meningful relief t t=30, 60, 90, 120 min Groups Rndom Effect OR (95% CI) Cochrn Q I² (inconsistency) T=30 min IBU T vs 1.89 ( ) n.s. n.s. vs 5.90 ( ) n.s. n.s. vs IBU T 3.14 ( ) T=60 min IBU T vs 2.76 ( ) % vs 31.9 ( ) n.s. n.s. vs IBU T 11.6 ( ) T=90 min IBU T vs 2.85 ( ) % vs 55.8 ( ) n.s. n.s. vs IBU T 9.61 ( ) T=120 min IBU T vs 3.67 ( ) % vs 35.1 ( ) n.s. n.s. vs IBU T 9.56 ( ) Pooled dt re bsed on 3 studies for [13, 14, 30], nd on 4 studies for IBU T t t=90 min [7, 10, 34, 43], on 5 studies t t=30 min (+ [45]), nd on 6 studies t t=60, 120 min (+ [40]); n.s.: vlues re not significnt t the = 0.05 level; odd rtios of the djusted indirect comprison. 306

7 The differences between the products ws not significnt t 30 min post-dose, but becme significnt in fvour of for ll subsequent times. Significnt level of heterogeneity is observed in the outcome of time to rech MPR with the IBU T dt t ll times, with the exception of 30 min post dose. At 2 h post dose, for exmple, the Cochrn-Q test significntly indictes tht there is no single vlue for time to MPR tht the different IBU T studies re evluting, while the I 2 vlue suggests tht over 87% of the totl vrition cross studies is due to heterogeneity rther thn chnce. No publiction bis ws detected by the Egger test except for the OR of IBU T ginst plcebo t 2 h post-dose (dt not reported). Totl pin relief nd proportion of ptients chieving t lest % pin relief Both IBU T nd were significntly more effective in relieving pin s mesured by TOTPAR (0-6 h) thn plcebo. The men pooled TOTPAR score for IBU T ws 13.5 (n=661, 8 studies) nd 14.9 (95% CI: 14.2, 15.7, n=379, 4 studies) for dt tht did not report vrince nd those tht did, respectively. This vlue ws 17.0 for (95% CI: 16.0, 18.0, n=126, 2 studies) (Tble 5). An independent Student s t-test [20] revels tht provided better pin relief s mesured by TOTPAR (0-6 h) thn tht chieved with IBU T, lthough, with smll effect size (two-tiled t-test, t(3)=2.9, p=0.0042, Cohen s d = 0.29). The vilble dt llowed clcultion of proportion of ptients with more thn % pin relief for 2 nd 8 IBU T studies ( totl of 9 included IBU T groups) (Tble 6). Significntly more ptients chieved t lest % totl pin relief over 6 h of dosing with either of IBU T or thn with plcebo, showing n odd rtio of 11.7 (95% CI: 5.20, 26.4) with IBU T nd 25.9 (95% CI: 11.4, 58.7) with ginst plcebo. No significnt difference ws observed between the two products when compred to ech other. The Cochrn-Q test indictes the presence of heterogeneity in the IBU T studies with regrds to this outcome nd the I 2 inconsistency tests ttributes over 80% of the vrition in the results to the heterogeneity or other forms of bis rther thn chnce. Tble 5. Totl pin relief (TOTPAR) score over 0 6 h Reference 400 mg IBU T 400 mg Reference N Men N Men N Men N Men [13] [39] c [31] [40] c [42] c Pooled e [37] b,c,d [37] b,c [34] d [10] d [38] [7] d Pooled e Pooled c Pooled d Stndrd devition () when vilble; b study hd two rms of ibuprofen; c studies which reported ; d studies which used Motrin IB; e significnt difference (two tiled Student s t test, t(3)=2.88, p=0.0042, Cohen s d = 0.29) Tble 6. Odd rtios nd heterogeneity for the outcome of chieving more thn % pin relief Groups Rndom Effect OR (95% CI) Cochrn Q I² (inconsistency) IBU T vs 11.7 ( ) % vs 25.9 ( ) n.s. n.s. vs IBU T 2.22 ( ) Pooled dt re bsed on two studies for [13, 31], nd on eight studies for IBU T [7, 10, 34, 37 40, 42]; n.s.: vlues re not significnt t the = 0.05 level; odd rtios of the djusted indirect comprison. 307

8 DISCUSSION The tsk of developing n nlgesic mediction with meningful onset of ction hs proven to be difficult if not impossible [22, 23]. This hs been ttributed to the gstric dysfunction tht is ssocited with pin or the trum of pin [22, 24]. Reports [22, 25, 26], except for one [27] suggest resonble correltion between nlgesics concentrtion in the circultion nd relief of pin. For n nlgesic to ct, however, the formultion hs to disintegrte nd dissolve before the ctive ingredient become vilble for bsorption through the gstrointestinl (GI) trct. Although, depending on the drug pk, the process my commence in the stomch, the min site of bsorption is the intestine. In the mentime, pin nd/or its trum cuses gstric dysfunction; i.e., reduced gstric motility, slow-down of gstric emptying nd reduced fluid excretion tht result in slow disintegrtion nd subsequent dissolution in the stomch [22]. Vrious commercilly vilble formultions, e.g., dissolved drug in soft geltin cpsules re climed to hve rpid GI bsorption, hence, quick onset of ction [13]. However, clinicl evidence suggestive of ccelerted onset of ction of products contining the sme ctive ingredient is nonexistent or not published. Recently, more rpid bsorption during episodes of pin hs been reported for formultions tht re not coted nd contin some disintegrtion ction, hence, their disintegrtion nd dissolution re less dependent on the gstric function [24]. Similrly, ccelerted onset of ction hs been reported for products with undisclosed formultions tht contin vrious slts of ibuprofen [28, 29]. However, such dt generted by studying ptients in pin re not publicly vilble for soft geltin cpsules. hs been compred with vrious other drugs for the mngement of pin ssocited with migrine, hedche, or dentl procedures including celecoxib [30], cetminophen [13, 14, 31], nd ketoprofen [13], but not with the other more solid formultions of ibuprofen. In the bsence of comprtive clinicl studies, systemtic reviews nd indirect met-nlysis comprisons remin to be effective mens of pprising clinicl evidence. Regrding desirble onset of ction, our nlysis of the vilble dt suggests, for the first time, few dvntges of liquigel over other vilble forms of ibuprofen. While the differences between products in FPPR were not significnt (Tble 2), yielded significntly fster MPR (Tble 3). Similrly, when ws compred with IBU T (OR=1), the OR for MPR ws greter thn unity (9.61 to 19.6) during min ssessment period. However, t 30 min this vlue ws not significntly elevted for (3.1; 95% CI: 0.90, 10.8). It is, therefore, resonble to suggest tht the liquigel exhibits fster onset of pin relief thn the other products. However, cler difference between the products ppers only t 60 min. In helthy subjects, plsm ibuprofen concentrtion peks much fster following orl dministrtion of (T mx, 30 min, [12]) thn other exmined products (T mx, 2 h, [32]). Ignoring the pthophysiologicl chnges in response to pin [22], such difference in the rte of bsorption is expected to result in significntly fster onset of nlgesi for s compred with IBU T. However, our nlysis suggests tht significntly greter response is only seen fter 60 min rther thn 30 min. This dely my be ttributed to the pininduced gstric dysfunction. In ddition, Jones et l [27] who correlted ibuprofen plsm concentrtion with its nlgesic effect following dministrtion of soluble form of the drug found no significnt link between the two vribles despite their T mx of 30 min. Therefore, the min resons for the dely in nlgesi following orl doses pper to include i) the pin-induced gstric dysfunction, hence, delyed bsorption nd ii) gp between erly rise in the drug plsm concentrtion nd its rrivl t the site of ction. When dministered in the form of solution, ibuprofen ppers to be bsorbed quickly independent of gstric dysfunction s T mx vlues of 25 nd 30 min hve been reported for both helthy subjects [32] nd ptients in pin [27], respectively. This is becuse the drug is vilble for bsorption without the delys cused by disintegrtion of tblets or opening of cpsule shell nd subsequent dissolution of the ctive ingredient. Bsed on our nlysis, it is resonble to suggest tht during episodes of pin, lthough both nd IBU T re subject to delyed bsorption due to the reported gstric dysfunction, the former provides fster relief of pin reltive to the ltter. In typicl clinicl trils of nlgesics smll popultions of ptients re employed (-100 ptients/study rm, Tble 1). Considering the inherent inter-subject vribility in such studies, much lrger popultion size is needed for relible results. By pooling the vilble clinicl tril dt tht hve tested the products of interest, s we hve done herein, the dt my be nlyzed with more sttisticl power. 308

9 While pproches re often dopted to minimize bis in systemtic reviews some sources of bis nd heterogeneity tht re inherent in the studies still exist [33]. In the eligible reports used in this nlysis, the brnd used is identified in 3 of the 4 nd only 7 out of 18 IBU T studies. This my ignore the potentil between-products vribility. For exmple, in our included reports we hd 5 sets of dt tht identified Motrin IB (Motrin, McNeil Consumer Helthcre, Fort Wshington PA, USA) s the brnd. We found shorter time to ttin MPR (52.0 min) s compred to the pooled dt (104.1 min) but still longer thn tht for IB LG (35.0 min) (Tble 3). Similrly, shorter FPPR vlues were observed for Motrin thn tht for the pooled IBU T so tht it rendered the difference between Motrin nd insignificnt (Tble 2). In our nlysis we included ll dt vilble generted from ptients with ll cute type of pin (Tble 1). However, the mjority of the reports hd included dentl pin. When we nlysed the vilble dt on the dentl pin only, we noticed very similr results except for FPPR tht indicted significnt difference between (10.2 min; 95% CI: 9.0, 13.8) nd IBU T (26.9 min; 95% CI: 20.4, 40.3). However, this difference ws bsed on only one study for tht reported FPPR for dentl pin. To mesure efficcy, we considered totl pin relief score (TOTPAR) over 6 h, which is n outcome mesure tht is commonly used in clinicl trils of nlgesi. It is bsed on summing ctegoricl pin relief scores (rnging from 0 to 4) for ll prticipnts t vrious time intervls fter dosing. The results (Tble 5) suggest tht provides significntly higher TOTPAR s compred with IBU T, but the size of this effect is smll (Cohen s d = 0.29). Another outcome mesured tht is useful in determining the effectiveness of pin relieving gents is the proportion of ptients with more thn % pin relief (bsed on TOTPAR). This outcome cn be computed ccording to liner regression fit tht hs been developed by Moore et l [21] to dichotomize the dt. The pooled odd rtio for this outcome did not indicte significnt difference between nd IBU T, which suggest tht the overll efficcy cross the 6 h post-dose ws comprble for both products. CONCLUSION The met-nlysis of the vilble clinicl dt suggests tht both solid tblets nd liquigel of ibuprofen re effective in controlling moderte to severe episodes of pin. The evidence, lthough not overwhelming, suggest fster onset of nlgesi for liquigel s compred with tblets. This informtion is timely in light of the ever incresing number of products in soft geltin cpsules ppering on the mrket. Well-powered comprtive clinicl trils re needed in this field. ACKNOWLEDEGMENTS AND CONFLICTS This reserch ws supported by University of Albert Self-Directed grnt. H.A. ws recipient of scholrship grnted by the government of Omn. Authors hve no conflict of interest regrding the contents of the pper. REFERENCES 1. Rinsford, K., History nd development of ibuprofen, in Ibuprofen: Discovery, Development nd Therpeutics. 2015, Wiley Blckwell: West Sussex UK. p Shrv, Y. nd R. Beoliel, Orofcil pin & hedche. 2008, Phildelphi: Elsevier Helth Sciences. 3. Emmi, J., In vitro in vivo correltion: from theory to pplictions. J Phrm Phrm Sci, (2): p Alvrez, C., et l., Investigtion on the possibility of biowivers for ibuprofen. J Phrm Sci., (6): p Klueglich, M., et l., Ibuprofen extrudte, novel, rpidly dissolving ibuprofen formultion: reltive biovilbility compred to ibuprofen lysinte nd regulr ibuprofen, nd food effect on ll formultions. J Clin Phrmcol, (9): p Evns, A.M., Comprtive Phrmcology of S(+)- Ibuprofen nd (RS)-Ibuprofen. 2001: 20(1): Clinicl Rheumtology, (1): p Mehlisch, D.R., A. Ardi, nd T. Pllott, A controlled comprtive study of ibuprofen rginte versus conventionl ibuprofen in the tretment of postopertive dentl pin. J Clin Phrmcol, (8): p Mehlisch, D.R., et l., Comprtive study of ibuprofen lysine nd cetminophen in ptients with postopertive dentl pin. Clin Ther, (5): p

10 9. Jywrden, S., R. Leyv, nd D. Kellstein, Sfety of novel formultion of ibuprofen sodium compred with stndrd ibuprofen nd plcebo. Postgrd Med, (1): p Desjrdins, P., et l., Ibuprofen rginte provides effective relief from postopertive dentl pin with more rpid onset of ction thn ibuprofen. Eur J Clin Phrmcol, (6): p Gullplli, R.P., Soft geltin cpsules (softgels). J Phrm Sci, (10): p Anonymous, Compendium of Phrmceuticls nd Specilities. 2009, Ottw, ON, Cnd: Cndin Phrmcists Assocition. 13. Olson, N., et l., Onset of nlgesi for liquigel ibuprofen 400 mg, cetminophen 1000 mg, ketoprofen 25 mg, nd plcebo in the tretment of postopertive dentl pin.. J Clin Phrmcol, (11): p Pckmn, B., et l., Solubilized ibuprofen: evlution of onset, relief, nd sfety of novel formultion in the tretment of episodic tension-type hedche. Hedche, : p Guyot, P., et l., Enhnced secondry nlysis of survivl dt: reconstructing the dt from published Kpln-Meier survivl curves. BMC Med Res Methodol, (9): p Lsk, E.M., C. Siegel, nd A. Sunshine, Onset nd durtion: mesurement nd nlysis. Clinicl Phrmcology & Therpeutics, (1): p Bucher, H.C., et l., The results of direct nd indirect tretment comprisons in met-nlysis of rndomized controlled trils. Journl of clinicl epidemiology, (6): p DerSimonin, R. nd N. Lird, Met-nlysis in Clinicl Trils. Controlled Clinicl Trils, : p Singh, N. nd P. Chng, A systemtic review of the sensitivity of efficcy endpoints TOTPAR nd SPID in cute pin. The Journl of Pin, (4): p. S Student, The probble error of men. Biometrik, 1908: p Moore, A., H. McQuy, nd D. Gvghn, Deriving dichotomous outcome mesures from continuous dt in rndomised controlled trils of nlgesics: verifiction from independent dt. Pin, : p Jmli, F. nd C.M. Kunz-Dober, Pin-medited ltered bsorption nd metbolism of ibuprofen: n explntion for decresed serum enntiomer concentrtion fter dentl surgery. Br J Clin Phrmcol, : p Almukinzi, M., et l., Disese specific modeling: Simultion of the phrmcokinetics of meloxicm nd ibuprofen in disese stte vs. helthy conditions. Eur J Phrm Biophrm, : p Jmli, F. nd A. Aghzdeh-Hbshi, Rpidly dissolving formultions for quick bsorption during pin episodes: ibuprofen. Interntionl Journl Of Clinicl Phrmcology nd Therpeutics, (2): p Lsk, E.M., et l., The correltion between blood levels of ibuprofen nd clinicl nlgesic response. Clin Phrmcol Ther, : p Seymour, R.A., P.J. Kelly, nd J.E. Hwkesford, Phrmcokinetics nd efficcy of low-dose ketoprofen in prospective dentl pin. Clin Drug Invest, : p Jones, K., R.A. Seymour, nd J.E. Hwkesford, Are the phrmcokinetics of ibuprofen importnt determinnts for the drug's efficcy in postopertive pin fter third molr surgery? British Journl of Orl nd Mxillofcil Surgery, (3): p Legg, T.J., et l., buprofen sodium is bsorbed fster thn stndrd Ibuprofen tblets: results of two openlbel, rndomized, crossover phrmcokinetic studies. Drugs R D, (4): p Lewis, D.W., et l., Children's ibuprofen suspension for the cute tretment of peditric migrine. Hedche: The Journl of Hed nd Fce Pin, (8): p Doyle, G., et l., Efficcy nd tolerbility of nonprescription ibuprofen versus celecoxib for dentl pin. J Clin Phrmcol, (8): p Hersh, E.V., et l., Ibuprofen liquigel for orl surgery pin. Clin The, (11): p Jmli, F., et l., Humn phrmcokinetics of ibuprofen enntiomers following different doses nd formultions: intestinl chirl inversion Journl of phrmceuticl sciences, (3): p Shrier, I., R.W. Pltt, nd R.J. Steele, Meg-trils vs. met-nlysis: Precision vs. heterogeneity? Contemporry clinicl trils, (3): p Blck, P., et l., A Rndomized, Double-Blind, -Controlled Comprison of the Anlgesic Efficcy, Onset of Action, nd Tolerbility of Ibuprofen Arginte nd Ibuprofen in Postopertive Pin. Clinicl Therpeutics, (7): p Li, H., et l., Modeling the Onset nd Offset of Pin Relief by Ibuprofen. Journl of Clinicl Phrmcology, : p Mlmstrom, K., et l., Comprison of Rofecoxib nd Celecoxib, Two Cyclooxygense-2 Inhibitors, in Postopertive Pin:A Rndomized, nd Active-Comprtor-Controlled Clinicl Tril. CLINICALTHERAPEUTICS, (10): p Brin, P., et l., Onset of Anlgesi nd Efficcy of Ibuprofen Sodium in Postsurgicl Pin: A Rndomized, -controlled Study Versus Stndrd Ibuprofen. Clin J Pin, (5): p

11 38. McQuy, H.J., et l., Ibuprofen compred with ibuprofen plus cffeine fter third molr surgery. Pin, : p Cheung, R., S. Krishnswmi, nd K. Kowlski, Anlgesic Efficcy of Celecoxib in Postopertive Orl Surgery Pin: A Single-Dose, Two-Center, Rndomized, Double-Blind, Active- nd - Controlled Study. Clinicl Therpeutics, (Theme Issue): p Dimond, S., T.K. Blm, nd F.G. Freitg, Ibuprofen plus cffeine in the tretment of tension-type hedche. CLINICAL PHARMACOLOGY & THERAPEUTICS, (3): p Mehlisch, D.R., et l., Comprison of the Anlgesic Efficcy of Concurrent Ibuprofen nd Prcetmol With Ibuprofen or Prcetmol Alone in the Mngement of Moderte to Severe Acute Postopertive Pin in Adolescents nd Adults: A Rndomized, Double-Blind, -Control. Clinicl Therpeutics, (5): p Dionne, R.A. nd L. McCullgh, Enhnced nlgesi nd suppression of plsm bet-endorphin by the S(+)-isomer of ibuprofen. CLINICAL, PHARMACOLOGY & THERAPEUTICS, (5): p Goldstein, J., et l., Acetminophen, Aspirin, nd Cffeine in Combintion Versus Ibuprofen for Acute Migrine: Results From Multicenter, Double-Blind, Rndomized, Prllel-Group, Single-Dose, - Controlled Study. Hedche, : p Morrison, B.W., et l., Anlgesic Efficcy of the Cyclooxygense-2-Specific Inhibitor Rofecoxib in Post- Surgery Pin: A Rndomized, Controlled Tril. Clinicl Therpeutics, (6): p Pckmn, E., R. Leyv, nd D. Kellstein, Onset of nlgesi with ibuprofen sodium in tension-type hedche: rndomized tril. Journl of Phrmceuticl Helth Cre nd Sciences, 2015: p Hill, C.M., et l., Pregblin in ptients with postopertive dentl pin. Europen Journl of Pin, : p Schwrtz, J.I., et l., MK-0703 ( Cyclooxygense-2 inhibitor) in Acute Pin Associted with Surgery: A Rndomized, Double-Blind, - nd Active Comprtor Controlled Dose-Rnging Study. Americn Journl of Therpeutics, : p Kleinert, R., et l., Single Dose Anlgesic Efficcy of Tpentdol in Postsurgicl Pin: The Results of Rndomized, Double-Blind, -Controlled Study. Anesth Anlg, : p Zelenks, K., et l., Anlgesic efficcy of single orl doses of lumircoxib nd ibuprofen in ptients with postopertive dentl pin. Int J Clin Prct, (3): p

12 Supplementry Mteril Study Control IBU Comprtor OR[95% CI] [30] [13] [14] [34] [10] [43] [7] [45] IBU T vs IBU T 1.88[0.36,18.73] 9.11[3.30,26.54] 24.18[1.88, ] 5.93[1.85,18.99] 1.70[0.89,3.26] 1.84[0.49,8.64] 1.76[0.58,7.12] 2.25[0.94,5.71] 7.40[0.48, ] 1.89[1.25,2.86] 3.14[0.91,10.81] Odd Rtio Study Control IBU Comprtor OR[95% CI] [30] [13] [14] [34] [10] [40] [43] [7] [45] IBU T vs IBU T 17.60[3.80,160.55] 28.13[7.70,123.41] 62.83[13.76,367.01] 31.88[14.58,69.70] 2.58[1.40,4.76] 1.38[0.47,4.09] 2.32[0.77,8.38] 1.49[0.93,2.46] 3.60[1.89,6.93] 12.47[4.,39.24] 2.76[1.58,4.82] 11.55[4.42,30.19] Odd Rtio () 30 min (b) 60 min Study Control IBU Comprtor OR[95% CI] [30] [13] [14] [34] [10] [43] [7] IBU T vs IBU T 47.20[9.52,433.12] 38.10[9.28,213.36] [20.47,665.85] 55.84[24.17,129.00] 4.00[2.10,7.68] 2.43[0.81,7.36] 1.36[0.94,1.97] 5.31[2.77,10.21] 2.85[1.36,6.00] 19.59[6.39,60.07] Odd Rtio Study Control IBU Comprtor OR[95% CI] [30] [13] [14] [34] [10] [40] [43] [7] [45] IBU T vs IBU T 28.42[7.47,127.66] 38.10[9.28,213.36] 41.80[9.43,242.43] 35.07[16.47,74.70] 5.23[2.65,10.] 3.94[1.24,12.49] 2.24[1.01,5.18] 1.27[0.92,1.76] 5.07[2.66,9.73] 9.98[3.96,25.60] 3.67[1.79,7.53] 9.56[3.37,27.13] Odd Rtio (c) 90 min (d) 120 min Figure 1S. Forest plots of the odd rtios of chieving meningful pin relief t () 30 min, (b) 60 min, (c) 90 min, nd (d) 120 post dose Study Control IBU Comprtor OR[95% CI] [13] [31] [39] [42] [40] [37] [34] [10] [38] [7] IBU T vs IBU T 38.76[11.01,1.60] 17.23[4.85,67.90] 25.89[11.42,58.68] 26.65[8.32,97.47] 12.46[2.54,116.70] 1.54[0.72,3.28] 32.06[11.92,98.32] 6.78[3.48,13.27] 32.05[2.24, ] 11.43[0.56, ] 8.87[4.20,19.44] 11.66[5.15,26.41] 2.22[0.69,7.06] Odd Rtio Figure 2S. Forest plot of the odd rtios of chieving t lest % pint relief bsed on TOTPAR 0-6 1s

13 Tble 1S. Section/topic # Checklist item Reported on pge # TITLE Title 1 Identify the report s systemtic review, met-nlysis, or both. It is both (pge 1) ABSTRACT Structured summry 2 Provide structured summry including, s pplicble: bckground; objectives; dt Done sources; study eligibility criteri, prticipnts, nd interventions; study pprisl nd synthesis methods; results; limittions; conclusions nd implictions of key findings; systemtic review registrtion number. INTRODUCTION Rtionle 3 Describe the rtionle for the review in the context of wht is lredy known. Lst line of pge 2 nd beginning of pge 3: However, results. Objectives 4 Provide n explicit sttement of questions being ddressed with reference to prticipnts, interventions, comprisons, outcomes, nd study design (PICOS). Pge 2, prgrph just before Methods We, therefore, ttempted to compre the onset of nlgesi nd efficcy of the liquigel with solid dosge forms of ibuprofen by undertking systemtic review nd met-nlysis of ll the studies tht report onset of nlgesi nd efficcy of ibuprofen fter dministrtion of these formultions for the tretment of dentl pin or migrine or tension-type hedche. METHODS Protocol nd registrtion 5 Indicte if review protocol exists, if nd where it cn be ccessed (e.g., Web ddress), nd, if vilble, provide registrtion informtion including registrtion number. Protocol is with uthors. The study is not registered 2s

14 Eligibility criteri 6 Specify study chrcteristics (e.g., PICOS, length of follow-up) nd report chrcteristics (e.g., yers considered, lnguge, publiction sttus) used s criteri for eligibility, giving rtionle. Pge 3-4, Methods, prgrphs 1&2: There ws lck. hours post dose Informtion sources 7 Describe ll informtion sources (e.g., dtbses with dtes of coverge, contct with study uthors to identify dditionl studies) in the serch nd dte lst serched. Serch 8 Present full electronic serch strtegy for t lest one dtbse, including ny limits used, such tht it could be repeted. Pge 3, first prgrph of Methods (lines 1-3) Pubmed serch terms: Ibuprofen AND onset AND study AND (dentl OR "migrine" OR "tension-type hedche" OR "orl surgery") Study selection 9 Stte the process for selecting studies (i.e., screening, eligibility, included in systemtic review, nd, if pplicble, included in the met-nlysis). Dt collection process 10 Describe method of dt extrction from reports (e.g., piloted forms, independently, in duplicte) nd ny processes for obtining nd confirming dt from investigtors. Pge 3 Presented in 2 nd prgrph of Methods: The review ws.. Pge 3: First prgrph of Methods. The screening nd eligibility ssessment of the reports ws crried out independently by the two uthors. Dt items 11 List nd define ll vribles for which dt were sought (e.g., PICOS, funding sources) nd ny ssumptions nd simplifictions mde. Risk of bis in individul studies 12 Describe methods used for ssessing risk of bis of individul studies (including specifiction of whether this ws done t the study or outcome level), nd how this informtion is to be used in ny dt synthesis. Pge 3. The 4 th nd 5 th prgrphs of Methods. Two mesures. Pge 3. First prgrph of Methods, The screening. Pge 4. Bottom of pge. Vrition mong studies ws nticipted, nd due to the heterogeneity. 3s

15 Summry mesures 13 Stte the principl summry mesures (e.g., risk rtio, difference in mens). Pge 4, 5:compring medins to FPPR nd MPR, OR of chieving meningful relief t 30, 60, 90, 120 min post dose, differences in men TOTPAR0-6, nd OR of chieving % or more pin relief bsed on TOTPAR. Synthesis of results 14 Describe the methods of hndling dt nd combining results of studies, if done, including mesures of consistency (e.g., I 2 ) for ech met-nlysis. Pges 4 & 5, Two mesures. Section/topic # Checklist item Reported on pge # Risk of bis cross studies 15 Specify ny ssessment of risk of bis tht my ffect the cumultive evidence (e.g., publiction bis, selective reporting within studies). Additionl nlyses 16 Describe methods of dditionl nlyses (e.g., sensitivity or subgroup nlyses, metregression), if done, indicting which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, ssessed for eligibility, nd included in the review, with resons for exclusions t ech stge, idelly with flow digrm. Study chrcteristics 18 For ech study, present chrcteristics for which dt were extrcted (e.g., study size, PICOS, follow-up period) nd provide the cittions. Risk of bis within studies 19 Present dt on risk of bis of ech study nd, if vilble, ny outcome level ssessment (see item 12). No evidence of bis ws found. The Egger test ws mesured but not reported Subgroup nlysis ws used for specific brnd (Motrin IB) Pge 5, prgrphs 1&2 nd Figure 1. Tble 1. Not reported s no bis ws found. 4s

16 Line dded to the end of section 3.2. No publiction bis ws detected by the Egger test except for the OR of ginst plcebo t 2 h post-dose (dt not reported). Results of individul studies 20 For ll outcomes considered (benefits or hrms), present, for ech study: () simple summry dt for ech intervention group (b) effect estimtes nd confidence intervls, idelly with forest plot. Synthesis of results 21 Present results of ech met-nlysis done, including confidence intervls nd mesures of consistency. Forest plots of the odd rtios re dded s supplementry figures Tbles 4,6 Risk of bis cross studies 22 Present results of ny ssessment of risk of bis cross studies (see Item 15). Egger test ws used to ssess publiction bis nd the results re described., (dt re not reported) Additionl nlysis 23 Give results of dditionl nlyses, if done (e.g., sensitivity or subgroup nlyses, metregression [see Item 16]). DISCUSSION Summry of evidence 24 Summrize the min findings including the strength of evidence for ech min outcome; consider their relevnce to key groups (e.g., helthcre providers, users, nd policy mkers). Limittions 25 Discuss limittions t study nd outcome level (e.g., risk of bis), nd t review-level (e.g., incomplete retrievl of identified reserch, reporting bis). Conclusions 26 Provide generl interprettion of the results in the context of other evidence, nd implictions for future reserch. Motrin IB dt given on pge 11 top 2 lines Min findings re summrized nd incorported within the discussion (pges 8-11) Lst prgrph on pge 10: While pproches.. This is lso crried out in the discussion (pges 8-11) 5s

17 FUNDING Funding 27 Describe sources of funding for the systemtic review nd other support (e.g., supply of dt); role of funders for the systemtic review. From: Moher D, Liberti A, Tetzlff J, Altmn DG, The PRISMA Group (2009). Preferred Reporting Items for Systemtic Reviews nd Met-Anlyses: The PRISMA Sttement. PLoS Med 6(7): e doi: /journl.pmed For more informtion, visit: sttement.org. 6s