Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain

RESEARCH ARTICLE Open Access Dexke op o en/ amadol: andomised double-blind ial and con i ma ion o empi ical heo y o combina ion analgesics in acu e pain R. And ew Moo e 1* , C. Gay-Escoda 2 , R. Figuei edo 2 , Z. Tó h-Bagi 3 , T. Die ich 4 , S. Mille i 5 , D. To es-Laga es 6 , C. M. Hill 7 , A. Ga cía-Ga cía 8 , P. Coul ha d 9 , A. Woj owicz 10 , D. Ma enko 10 , M. Peña ocha-Diago 11 , S. Cuad ipani 12 , B. Pizà-Vallespi 12 , C. Gue e o-Bayón 12 , M. Be olo i 13 , M. P. Con ini 13 , S. Sca oni 13 , A. Nizza do 13 , A. Cap ia i 13 and C. A. Maggi 13 Abs ac Backg ound: Combina ion analgesics a e e ec i e in acu e pain, and a heo e ical amewo k p edic s e icacy o combina ions. The combina ion o dexke op o en and amadol is un es ed, bu p edic ed o be highly e ec i e. Me hods: This was a andomised, double-blind, double-dummy, pa allel-g oup, placebo-con olled, single-dose ial in pa ien s wi h mode a e o se e e pain ollowing hi d mola ex ac ion. The e we e en ea men a ms, including dexke op o en ome amol (12.5 mg and 25 mg) and amadol hyd ochlo ide (37.5 mg and 75 mg), gi en as ou di e en ixed combina ions and single componen s, wi h ibup o en 400 mg as ac i e con ol as well as a placebo con ol. The s udy objec i e was o e alua e he supe io analgesic e icacy and sa e y o each combina ion and each single agen e sus placebo. The p ima y ou come was he p opo ion o pa ien s wi h a leas 50 % max TOTPAR o e six hou s. Resul s: 606 pa ien s we e andomised and p o ided a leas one pos -dose assessmen . All combina ions we e signi ican ly be e han placebo. The highes pe cen age o esponde s (72 %) was achie ed in he dexke op o en ome amol 25 mg plus amadol hyd ochlo ide 75 mg g oup (NNT 1.6, 95 % con idence in e al 1.3 o 2.1). Addi ion o amadol o dexke op o en esul ed in g ea e peak pain elie and g ea e pain elie o e he longe e m, pa icula ly a imes longe han six hou s (median du a ion o 8.1 h). Ad e se e en s we e un ema kable. Conclusions: Dexke op o en ome amol 25 mg combined wi h amadol hyd ochlo ide 75 mg p o ided good analgesia wi h apid onse and long du a ion in a model o mode a e o se e e pain. The esul s o he dose inding s udy a e consis en wi h p e- ial calcula ions based on empi ical o mulae. T ial egis a ion: Eud aCT (2010-022798-32); Clinical ials.go (NCT01307020). Keywo ds: Dexke op o en; T amadol; Combina ion analgesics; Pos ope a i e pain; Thi d mola ; Randomised con olled ial; Dose ange * Co espondence: [email p o ec ed] 1 Pain Resea ch and Nu ield Di ision o Anaes he ics, Nu ield Depa men o Clinical Neu ology, Uni e si y o Ox o d, The Chu chill, Ox o d OX3 7LE, UK Full lis o au ho in o ma ion is a ailable a he end o he a icle © 2015 Moo e e al. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/4.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly c edi ed. Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 DOI 10.1186/s10194-015-0541-5 Backg ound G ea e e icacy om combina ion analgesics in acu e pain has been ecognised o some ime [1], albei o iginally in cance pain. When o al analgesic d ugs a e es ed in s anda d, acu e pain models [2] hose wi h he highes e icacy and lowes numbe s-needed- o- ea (NNT) a e ypically high doses o indi idual analgesics o low doses o combina ions o analgesics [3]. Combina ions o d ugs o high e icacy include pa ace amol and codeine [4], pa ace amol and oxycodone [5], ibup o en and codeine [6], ibup o en and oxycodone [7], and ibup o en and pa ace amol [8]. E en adding ca eine can imp o e analgesic e icacy as a combina ion wi h con en ional analgesics [9]. The e icacy o combina ion analgesics has been shown o be he sum o he e icacies o he indi idual analgesic componen s, and was b oadly ue ac oss a ange o di e en d ug combina ions, in pos ope a i e pain and mig aine headache, and when es ed in he same and di e en ials [10]. This means ha he e icacy o any p oposed combina ion can be assessed heo e ically be o e clinical ials a e conduc ed. A po en ial pa o any combina ion migh be a as - ac ing non-s e oidal an i-in lamma o y d ug (NSAID) o mula ion, because speed o abso p ion and onse p oduces good and long las ing analgesia [11, 12]. Dexke op o en is e ec i e in acu e pain a low doses [13], and is also e ec i e in a wide a ie y o pain con- di ions [14]; dexke op o en is he ac i e chi al o m o ke op o en. T amadol is a widely used opioid o p o en e icacy in combina ion wi h pa ace amol [15]. This s udy he e o e aimed a e alua ing he supe io analgesic e icacy and sa e y o dexke op o en ome amol and amadol hyd ochlo ide gi en as ou di e en ixed combina ions and as single componen s in compa ison o placebo, on mode a e o se e e acu e pain ollowing impac ed hi d mandibula mola oo h ex ac ion. I was also in ended o selec he op imum dose combina ion(s) o be u he e alua ed in he subsequen phase III pi o al s udies. We used a o mula de i ed empi ically o es ima e he possible e icacy ha migh be ob ained om dexke o- p o en and amadol dosing combina ions [10]. The e we e limi ed da a o dexke op o en om a sys ema ic e iew [13] and wo indi idual pa ien le el analyses o amadol [16, 17]. Es ima ed NNTs o combina ions wi h dexke op o en ome amol 25 mg and amadol hyd ochlo ide 37.5 mg o 75 mg we e 2.2 and 1.6, espec i ely. Es ima es o combina ions wi h lowe dexke op o en ome amol doses (12.5 mg) we e highe (wo se) han 3 o abo e. The e was limi ed con idence in he NNT es ima es o he combina ions due o unce ain y in he e icacy es ima es o indi idual d ugs because o low numbe s. Me hods The s udy (Sponso Code DEX-TRA-02; Eud aCT num- be 2010-022798-32) was egis e ed a clinical ials.go (NCT01307020). I was pe o med a 16 s udy si es in six Eu opean coun ies (Ge many, Hunga y, I aly, Poland, Spain and he Uni ed Kingdom). I was conduc ed in acco dance wi h he p inciples o Good Clinical P ac ice and he Decla a ion o Helsinki and was app o ed by all he conce ned Compe en Au ho i ies and E hics Commi ees. All pa icipa ing pa ien s p o ided w i en in o med consen . The clinical phase o he s udy s a ed on 23 d Feb ua y 2011 ( i s pa ien sc eened) and concluded on 14 h Oc obe 2011 (las pa ien ou ). Pa ien s Heal hy male o emale pa ien s, aged 18 o 70 yea s, we e eligible o he s udy i hey we e scheduled o ou pa ien su gical emo al, unde local anaes hesia, o one o mo e hi d mola s, a leas one o which was ully o pa ially impac ed in mandibula bone. C i e ia o andomisa ion included pos ope a i e pain o mode a e o se e e in ensi y (Visual Analogue Scale [VAS] ≥40 mm and 4-poin Ve bal Ra ing Scale [VRS] ≥2) wi hin ou hou s a e su ge y. Pa ien s we e excluded om he s udy in any o he ollowing ci cums ances: p egnan o b eas eeding women o women o child-bea ing po en ial no using adequa e con acep ion; known alle gy o he s udy d ugs, pa ace a- mol, ace ylsalicylic acid, opioids o o he NSAIDs; mode a e o se e e enal, hepa ic o ca diac dys unc ion; his o y o gas oin es inal diso de s, bleeding diso de s; epilepsy, as hma, angioedema o ela ed diso de s; his o y o d ug o alcohol abuse; p esence o any medical condi ion ha in he opinion o he in es iga o migh pose a isk o he pa ien , may con ound s udy esul s o migh impai compliance wi h he s udy p ocedu es. Pa ien s who had ecei ed any in es iga ional d ug o pa icipa ed in any o he clinical ial wi hin he p e ious mon h we e also excluded. Fu he exclusion c i e ia included signi ican su gical complica- ions, o e all su ge y du a ion longe han one hou and need o e-anaes hesia. Pa ien s who had aken any analge- sics less han 24 h be o e su ge y we e also excluded. Concomi an use o alcohol, psychoac i e d ugs, seda i es and any o he medica ions o he apies ha could pose a isk o he pa ien o con ound he s udy esul s we e no pe mi ed wi hin 48 h and wo weeks be o e su ge y (de- pending on he hal li e o he espec i e medica ions) and up o 24 h pos -dose. Local applica ion o ice and he in ake o ca eine we e no pe mi ed du ing he 24-hou pos - dose pe iod. Pa ien s had o be in as ing condi ions om wo hou s be o e su ge y and up o h ee hou s pos -dose. S udy design This was a mul icen e, andomised, double-blind, double- dummy, pa allel-g oup, placebo-con olled, single-dose, Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 2 o 13 phase II, dose- inding s udy, wi h a o al o 10 ea men a ms (wi h balanced alloca ion a io), including dex- ke op o en ome amol (12.5 mg and 25 mg) and amadol hyd ochlo ide (37.5 mg and 75 mg) gi en as ou di e en ixed combina ions (DKP12.5/TRAM37.5; DKP12.5/TRAM75; DKP25/TRAM37.5; DKP25/TRAM75) and as single componen s (DKP12.5; DKP25; TRAM37.5; TRAM75). An ac i e con ol (ibup o en 400 mg, as an acid o mula ion) was included in o de o demons a e he sensi i i y o he pain model, because i was signi ican ly supe io o placebo in ials in he same indica ion [18–20], and has he la ges body o da a o he indica ion [3]. The o e all s udy du a ion was app oxima ely 30 days o each pa ien , including h ee isi s o he s udy si e: Visi 1, o sc eening (wi hin wo weeks o hei scheduled su ge y day); Visi 2, o den al su ge y, andomisa ion and ea men adminis a ion, ollowed by a 24-hou pos -dose pain and analgesic e ec assessmen pe iod (wi h he i s ou hou s a he s udy si e), du ing which pa ien s had o eco d e icacy da a using an elec onic dia y (eDia y); and Visi 3 (End o S udy), o inal sa e y ollow-up (10 ± 3 days a e su ge y day). In addi ion, pa ien s ecei ed a phone call o sa e y assess- men he day a e Visi 2 (app oxima ely 24 h pos -dose). Fo hose pa ien s who me he selec ion c i e ia, he su gical p ocedu e was pe o med unde s anda dised local anaes hesia, which was limi ed o local anaes he ic block using lidocaine (2 %) wi h epineph ine (1:80.000) up o a o al olume o 5.4 mL pe mola . A e su ge y, pa ien s epo ing pain we e asked o a e hei pain in ensi y (PI) by a VAS (0–100; wi h he le end labelled “no pain”and he igh end labelled “wo s possible pain”; [21, 22]) and by a 4-poin VRS (0 = none, 1 = mild, 2 = mode a e, 3 = se e e; [21]) o assess hei eligibili y o andomisa ion. Pa ien s expe iencing pain o mode a e o se e e in ensi y (VAS ≥40 mm and VRS ≥2) wi hin ou hou sa e heendo su ge ywe e andomisedand ecei ed one single o al dose o he assigned s udy ea men . A e andomisa ion and immedia ely p io o he adminis a ion o s udy medica ion, VRS-PI was measu ed again and he sco e was eco ded as baseline PI o he e icacy analysis. Pa icipan s we e andomly assigned o one o 10 ea men g oups ollowing a blocked andomisa ion p ocedu e, wi h a block size o 10 and an alloca ion a io o 1:1:1:1:1:1:1:1:1:1. The andomisa ion p ocess was cen alised by an In e ac i e Voice/Web Response Sys em (IVRS/IWRS) and he ea men code was deli e ed o each pa ien acco ding o a compu e - gene a ed andom alloca ed sequence ( andomisa ion lis ) p epa ed by a Sponso ’s hi d pa y p io o he s a o he s udy. Two se s we e p epa ed, one se was used o p og amming he IVRS/IWRS and he o he se was used o he labelling o he s udy medica ion. Pe sonnel in ol ed in he p epa a ion o he handling o he an- domisa ion lis we e no in ol ed in he s udy conduc and s a is ical analysis. Double-blind condi ions we e secu ed by he iden ical appea ance and weigh o he eigh es ed s udy d ugs as able s as well as he placebo able ma ching he es ed s udy d ugs. In o de o keep he ac i e con ol ibup o en blinded, he e was also a placebo able ma ching ibup o en (each single-dose ea men consis ed o wo able s) leading o a double- dummy design. The blind was main ained o pa ien s and o people esponsible o he ongoing conduc o he s udy (such as he managemen , moni o s, in es iga o s) and hose esponsible o da a analysis and in e p e - a ion o esul s a he conclusion o he s udy, such as biome ics pe sonnel. Rescue medica ion (RM) consis ing o pa ace amol 1 g (wi h a maximum ecommended daily dose o 4 g) was a ailable on eques du ing he 24-hou pos -dose pe iod. Pa ien s we e encou aged bu no compelled o wai o a leas 60 min pos -dose, o allow ime o he s udy medica ion o ake e ec . E icacy e alua ion Following ea men adminis a ion, pa ien s we e e- ques ed o make mul iple assessmen s o pain in ensi y and pain elie (PAR) on he eDia y o e a pe iod o 24 h. They also had o make an o e all assessmen o he s udy medica ion (pa ien global e alua ion, PGE) a he end o his pe iod. The ime when RM was i s used, i applicable, was also eco ded. PI was measu ed on a 4-poin VRS (0 = none, 1 = mild, 2 = mode a e, 3 = se e e; [21]) immedia ely p io he adminis a ion o s udy medica ion (baseline PI) and hen a 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 8 h, 12 h and 24 h pos -dose. PAR was measu ed on a 5-poin VRS (0 = none, 1 = sligh , 2 = mode a e, 3 = good, 4 = comple e; [21]) a he same p e-de ined pos -dose ime poin s. PGE was measu ed on a 5-poin VRS (1 = poo , 2 = ai , 3 = good, 4 = e y good, 5 = excellen ; [21, 23]) a 24 h pos -dose (o whene e he pa ien used RM, i his occu ed i s ). When pa ien s used RM, a inal PI and PAR assessmen and he PGE we e eco ded immedia ely be o e he in ake and, a e ha , hey we e excluded om u he e icacy measu emen s. A e use o RM, he baseline obse a ion ca ied o wa d (BOCF) me hod was applied [24], wi h PI e u ning o i s baseline sco e and PAR o ze o o all subsequen ime poin s. I a pa ien p ema u ely wi hd ew om he s udy, inal PI and PAR assessmen and he PGE we e also eques ed. F om he PI and PAR sco es, he summed pain in ensi y di e ences (SPID) and he o al pain elie (TOTPAR) o e 4, 6, 8 and 12 h pos -dose we e calcula ed. SPID was calcula ed as he ime-weigh ed sum o he pain in ensi y Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 3 o 13 di e ence (PID) alues om baseline and TOTPAR was calcula ed as he ime-weigh ed sum o he PAR sco es. The pe cen ages o he heo e ical maximum possible SPID (% max SPID) and o he heo e ical maximum possible TOTPAR (% max TOTPAR) we e also calcula ed. The p ima y e icacy endpoin was he pe cen age o pa ien s showing esponse, de ined as he achie emen o a leas 50 % o he maximum possible TOTPAR (≥50 % max TOTPAR), o e 6 h pos -dose wi hin he espec i e ea men a m [3, 24]. Seconda y e icacy endpoin s included: pe cen age o esponde s (≥50 % max TOTPAR) o e 4, 8 and 12 h; mean PI and PAR (VRS) sco es o e 24 h; SPID, % max SPID, TOTPAR and % max TOTPAR o e 4, 6, 8 and 12 h; PGE a he end o he assessmen pe iod; ime o i s use o RM since ea men adminis a ion and pe cen age o pa ien susingRMo e 4,6,8,12and24h. Sa e y e alua ion The sa e y e alua ion was based on he incidence, se iousness, in ensi y and causal ela ionship o ea men - eme gen ad e se e en s (AEs). AEs we e assessed h oughou he en i e s udy by means o a non-leading open ques ion. Spon aneously epo ed AEs we e also eco ded. Fu he mo e, sa e y was also e alua ed by he assessmen o clinically signi ican changes pos -dose e sus baseline in physical examina ion, i al signs (VS; blood p essu e and hea a e), 12-lead elec oca dio- g am (ECG) and labo a o y sa e y es s (haema ology, biochemis y and u inalysis). Any pa ien who p ema- u ely wi hd ew a e ha ing ecei ed s udy medica ion was encou aged o unde go Visi 3. S a is ical analysis Fo he p ima y e icacy a iable, in o de o demons a e he supe io i y o ac i e ea men in compa ison wi h placebo he null hypo hesis o equali y be ween placebo and each es ed s udy d ug ( he ou combina ions and he ou co esponding single agen s) was es ed using a Chi-squa e es . Mul iplici y was adjus ed by using he Šidák co ec ion [α=1-(1- α) ^ (1/k)], whe e k was he numbe o compa isons. Conside ing eigh compa isons, a ype I e o p obabili y = 0.00639 was used o he single compa isons. The null hypo hesis o equali y be ween placebo and he ac i e con ol was also es ed o alida e he pain model. In addi ion, e en a es (ER), ela i e isk (RR), NNT and ela i e isk educ ion (RRR), wi h hei co esponding 95 % con idence in e als (CI), we e es ima ed in o de o compa e he e ec size o placebo wi h he e ec size o each ac i e ea men . Seconda y e icacy a iables we e analysed as ollows: pe cen age o esponde s o e 4, 8 and 12 h we e analysed analogously o he p ima y e icacy a iable; mean PI and PAR (VRS) sco es we e analysed by means o desc ip i e s a is ics; quan i a i e a iables (TOTPAR, % max TOTPAR, SPID and % max SPID) showing homogenei y o a iance (acco ding o Le ene’s es ) we e analysed by one-way analysis o a iance (ANOVA) using he Dunne ’s es o compa ison be ween placebo and each ac i e ea men , wi h an o e all signi i- cance le el o 5 % wo-sided; o dinal a iables (PGE) and quan i a i e a iables showing no homogenei y o a iance we e analysed by he Wilcoxon ank-sum es o compa ison be ween placebo and each ac i e ea men , using he Hochbe g co ec ion o he adjus men o mul iple compa isons, wi h an o e all signi icance le el o 5 % wo-sided; ime o RM was analysed using he Kaplan-Meie es ima ion me hod and ea men g oups we e compa ed using a log- ank es , wi h he Hochbe g me hod applied o he mul iplici y co ec ion; pe cen age o pa ien s using RM we e analysed analogously o he p ima y e icacy a iable. Sa e y a iables we e analysed by means o desc ip i e s a is ics. As an explo a o y analysis, he p ima y e icacy endpoin was eassessed using ac i e con ol as compa a o . The s a is ics es was used o e alua e i he e ec o dexke o- p o en, amadol and hei combina ion was s a is ically signi ican on he ou come. When a leas one o he h ee es s was ound o be s a is ically signi ican , he Tukey me hod was applied o ind ou which doses ga e a signi ican di e ence on he ou come. S a is ical di e ences be ween NNTs we e examined using he z- es [25]. All e icacy analyses we e pe o med on he “in en ion- o- ea ”(ITT) popula ion ( andomised pa ien s who ecei ed s udy medica ion and o whom a leas one pos -dose assessmen was a ailable). The “pe p o ocol” (PP) popula ion (pa ien s o he ITT popula ion wi h no majo p o ocol iola ions) was used o pe o m con i ma- o y analyses on he p ima y endpoin . Sa e y analyses we e pe o med on he “sa e y”popula ion ( andomised pa ien s who ecei ed s udy medica ion). I was es ima ed ha 540 e aluable pa ien s (60 pe ea men a m) would ha e o be included in o de o achie e app oxima ely 80 % powe in ejec ing he null hypo hesis o equali y be ween placebo and he eigh expe imen al ea men a ms ( he ou combina ions and he ou co esponding single agen s) ega ding he p ima y endpoin , on he basis o he ollowing assump ions [26]: esponse a e o placebo = 0.13; expec ed RR o esponse in ac i e ea men e sus placebo = 3.21; o e all ype I e o p obabili y o 0.05 ( wo-sided). Six y u he pa ien s we e o be ea ed wi h he ac i e con ol as a e e ence o he e ec o he eigh expe imen al ea men a ms. I was expec ed ha app oxima ely 667 pa ien s would ha e o be sc eened in o de o ob ain 600 andomised pa ien s, assuming an app oxima e a e o 10 % sc eening ailu es. Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 4 o 13 Resul s O he 745 pa ien s sc eened, 611 pa ien s we e an- domised and ecei ed he s udy ea men , hus con- s i u ing he sa e y popula ion. E icacy analyses we e pe o med on he ITT popula ion o 606 andomised pa ien s. The PP popula ion o 567 pa ien s was used o pe o m con i ma o y analyses on he p ima y end- poin . Pa ien assignmen o he di e en popula ions occu ed be o e he s udy blind was b oken. The pa ici- pan low wi h he numbe s o pa icipan s who we e andomly assigned, ecei ed in ended ea men , and we e analysed o he p ima y ou come is ep esen ed in Addi ional ile 1. Demog aphy and baseline cha ac e is ics o di e en ea men g oups we e compa able. Demog aphic and baseline cha ac e is ics o he ITT popula ion a e ep e- sen ed in Table 1. The o e all mean age was 27 yea s ( ange 18–64 yea s), 59 % we e women, and 90 % we e whi e. The mean su ge y ime was 29 min, mos pa ien s (90 %) had only one mandibula mola emo ed, and he o al numbe o mola ex ac ions was one o wo in 95 % o pa ien s. Ini ial pain (baseline PI) was mode a e o se e e in 601 pa ien s (Table 2). Fou (0.65 %) pa ien s, ou o 611 andomised, discon- inued he s udy a e andomisa ion, hus esul ing in a o al o 607 pa ien s comple ing he s udy. One pa ien (alloca ed o DKP12.5/TRAM75) discon inued he s udy due o “ ailu e o eDia y”. The o he h ee pa ien s (alloca ed espec i ely o DKP25/TRAM37.5, DKP25/ TRAM75 and TRAM37.5) we e “los o ollow-up”. Th ee o hese ou pa ien s a ended Visi 3. E icacy esul s P ima y endpoin The pe cen age o pa ien s wi h ≥50 % max TOTPAR o e six hou s pos -dose was signi ican ly supe io o pla- cebo o all DKP/TRAM combina ions and also o DKP25 (p< 0.0001 o each compa ison, excep p=0.0009 o DKP12.5/TRAM37.5), wi h he highes pe cen age o esponde s achie ed in he DKP25/TRAM75 g oup (72 % e sus 10 % in he placebo g oup; Fig. 1 and Addi ional ile 2. De ailed ER, RR and NNT esul s a six hou s a e p esen ed in Addi ional ile 3. DKP25/TRAM75 also had he highes RR [7.2 (95 % CI: 3.3 o 15.7)] and he lowes NNT [1.6 (95 % CI: 1.3 o 2.1)]. No o he poin es ima e o NNT was below 2.0 (Fig. 2). The NNT o DKP25/TRAM75 was signi ican ly be e han o he NNT alues (p< 0.05, z- es ), excep o DKP25/ TRAM37.5, DKP12.5/TRAM75 and DKP25. The pe cen age o esponde s (≥50 % max TOTPAR) was signi ican ly supe io o placebo o all DKP/TRAM combina ions and o bo h doses o DKP in mono he apy (p< 0.0001) o e ou hou s and i emained signi ican ly supe io o DKP25/TRAM75, DKP12.5/TRAM75, DKP25/ TRAM37.5 (p< 0.0001) and DKP25 (p= 0.0012) o e eigh hou s; and o DKP25/TRAM75 (p= 0.0002), DKP12.5/ TRAM75 (p= 0.0004) and DKP25/TRAM37.5 (p=0.0028) o e 12 h. The highes pe cen age o esponde s o e ou , eigh and 12 h was achie ed wi h DKP25/TRAM75 (79 %, 54 % and 38 % espec i ely) e sus 6.5 % wi h placebo. Resul s a e ep esen ed in Addi ional ile 4 and Addi ional ile 5. The ac i e con ol, ibup o en 400 mg, was s a is ically supe io o placebo (p< 0.0001), hus alida ing he pain model. Analyses un on he PP popula ion con i med he p ima y e icacy esul s. Seconda y endpoin s The ime cou se o mean PAR and PI o e he whole 24 h pos -dose demons a ed apid onse o pain elie wi h dexke op o en alone o in combina ion, and ha he addi ion o amadol o dexke op o en esul ed bo h in g ea e peak pain elie and g ea e pain elie o e he longe e m, pa icula ly a imes longe han six hou s pos dose (Fig. 3, and Addi ional ile 6). The analysis o summa y e icacy measu es (SPID, % max SPID, TOTPAR and % max TOTPAR; Addi ional ile 7, Addi ional ile 8, Addi ional ile 9, Addi ional ile 10 and Addi ional ile 11) showed ha all DKP/TRAM com- bina ions and bo h doses o DKP in mono he apy we e signi ican ly supe io o placebo (p< 0.01) excep o DKP12.5 o e 12 h, wi h he bes esul s achie ed wi h DKP25/TRAM75. The ime cou se o mean SPID and mean TOTPAR a e ep esen ed in Addi ional ile 12 and Addi ional ile 13. The ime o RM was signi ican ly longe (p< 0.005) o all ac i e ea men s (excep o bo h doses o TRAM.HCl in mono he apy) han o placebo, wi h DKP12.5/TRAM75 and DKP25/TRAM75 p esen ing he longes alue (median ime, [95 % CI]: 8.5 h [5.9 o 13.0] and 8.1 h [6.3 o 13.4] espec i ely, e sus 1.4 h [1.2 o 1.8] in he placebo g oup). Fig. 4 shows he p opo ion o pa ien s emedica ing o e ime in each g oup, wi h addi ional in o ma ion in Addi ional ile 14 and Addi ional ile 15. The pe cen age o pa ien s equi ing RM (Addi ional ile 16 and Addi ional ile 17) o e ou and six hou s was signi ican ly smalle (p< 0.00639) o DKP12.5/TRAM75, DKP25/TRAM37.5, and DKP25/TRAM75 (also o DKP25 o e ou hou s) han o placebo (o e six hou s 47 %, 40 %, and 38 % o each combina ion espec i ely e sus 73 % o placebo). The di e ence emained signi ican o DKP25/TRAM75 o e eigh hou s (48 % e sus 73 %) and o DKP25/TRAM37.5 o e 12 and 24 h (49 % e sus 74 % o bo h ime poin s). The PGE o he s udy medica ion a he end o he assessmen pe iod is ep esen ed in Fig. 5. All ea - men s (excep TRAM37.5) we e signi ican ly supe io Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 5 o 13 Table 1 Demog aphic and baseline cha ac e is ics (ITT popula ion) DKP 12.5 mg + TRAM 37.5 mg DKP 12.5 mg + TRAM 75 mg DKP 25 mg + TRAM 37.5 mg DKP 25 mg + TRAM 75 mg DKP 12.5 mg DKP 25 mg TRAM 37.5 mg TRAM 75 mg Ibup o en Placebo O e all n 60 62 63 61 606059 59 6062606 Gende n (%) emale 34 (56.7) 38 (61.3) 36 (57.1) 34 (55.7) 36 (60.0) 43 (71.7) 38 (64.4) 27 (45.8) 40 (66.7) 33 (53.2) 359 (59.2) male 26 (43.3) 24 (38.7) 27 (42.9) 27 (44.3) 24 (40.0) 17 (28.3) 21 (35.6) 32 (54.2) 20 (33.3) 29 (46.8) 247 (40.8) E hnic o igin n (%) Whi e 56 (93.3) 57 (91.9) 56 (88.9) 59 (96.7) 54 (90.0) 51 (85.0) 56 (94.9) 52 (88.1) 49 (81.7) 57 (91.9) 547 (90.3) Asian 2 (3.3) 2 (3.2) 5 (7.9) 2 (3.3) 5 (8.3) 6 (10.0) 3 (5.1) 2 (3.4) 5 (8.3) 2 (3.2) 34 (5.6) Black 2 (3.3) 2 (3.2) 1 (1.6) 0 (0.0) 1 (1.7) 2 (3.3) 0 (0.0) 4 (6.8) 5 (8.3) 2 (3.2) 19 (3.1) O he 0 (0.0) 1 (1.6) 1 (1.6) 0 (0.0) 0 (0.0) 1 (1.7) 0 (0.0) 1 (1.7) 1 (1.7) 1 (1.6) 6 (1.0) Age (yea s) mean (SD) 28.7 (7.71) 27.0 (7.66) 26.3 (7.33) 27.3 (7.55) 27.0 (9.85) 27.0 (6.94) 25.5 (7.15) 27.9 (8.04) 26.7 (6.48) 26.1 (6.64) 26.9 (7.57) ange 18–52 18–53 18–64 18–52 18–63 18–48 18–55 18–58 18–44 18–54 18–64 BMI (kg/m 2 ) mean (SD) 23.7 (3.38) a 24.1 (3.69) 23.0 (2.87) 23.2 (3.19) 23.6 (3.20) 23.6 (3.30) b 23.0 (3.19) 24.2 (3.10) 22.4 (3.06) 22.7 (2.80) 23.3 (3.21) ange 18–30 18–35 18–32 18–30 18–30 15–30 18–30 18–34 18–31 18–29 18–35 Su ge y du a ion c mean (SD) 29:02 (14:40) 28:45 (12:58) 29:35 (17:32) 30:57 (16:39) 29:01 (12:03) 29:39 (14:45) 27:10 (11:10) 27:37 (14:01) 29:56 (13:31) 32:28 (15:23) 29:26 (14:23) To al hi d mola ex ac ions d n (%) 1 38 (63.3) 40 (64.5) 38 (60.3) 38 (62.3) 41 (68.3) 38 (63.3) 36 (61.0) 35 (59.3) 31 (51.7) 35 (56.5) 370 (61.1) 2 17 (28.3) 20 (32.3) 23 (36.5) 18 (29.5) 17 (28.3) 20 (33.3) 22 (37.3) 21 (35.6) 26 (43.3) 22 (35.5) 206 (34.0) 3 3 (5.0) 0 (0.0) 0 (0.0) 2 (3.3) 0 (0.0) 1 (1.7) 1 (1.7 ) 2 (3.4) 2 (3.3) 3 (4.8) 14 (2.3) 4 2 (3.3) 2 (3.2) 2 (3.2) 3 (4.9) 2 (3.3) 1 (1.7) 0 (0.0) 1 (1.7) 1 (1.7) 2 (3.2) 16 (2.6) Lowe hi d mola ex ac ions n (%) 1 54 (90.0) 55 (88.7) 56 (88.9) 53 (86.9) 55 (91.7) 53 (88.3) 56 (94.9) 52 (88.1) 53 (88.3) 57 (91.9) 544 (89.8) 2 6 (10.0) 7 (11.3) 7 (11.1) 8 (13.1) 5 (8.3) 7 (11.7) 3 (5.1) 7 (11.9) 7 (11.7) 5 (8.1) 62 (10.2) BMI body mass index a n= 59; b n= 59; c ime is exp essed in minu es and seconds; d o al numbe o hi d mola ex ac ions, including also uppe hi d mola ee h Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 6 o 13 Table 2 PI be o e andomiza ion and be o e ea men adminis a ion (ITT popula ion) DKP 12.5 mg + TRAM 37.5 mg DKP 12.5 mg + TRAM 75 mg DKP 25 mg + TRAM 37.5 mg DKP 25 mg + TRAM 75 mg DKP 12.5 mg DKP 25 mg TRAM 37.5 mg TRAM 75 mg Ibup o en Placebo O e all n 60 62 63 61 60 6059 59 6062606 PI be o e andomiza ion VAS Mean (SD) 58.28 (12.50) 57.74 (11.54) 56.25 (10.79) 57.72 (11.63) 58.33 (12:49) 57.72 (12.55) 57.10 (11:73) 56.32 (11.42) 57.33 (13:46) 60.34 (13.39) 57.72 (12.13) VRS Mode a e n (%) 48 (80.0) 53 (85.5) 48 (76.2) 48 (78.7) 45 (75.0) 47 (78.3) 56 (94.9) 47 (79.7) 51 (85.0) 46 (74.2) 489 (80.7) Se e e n (%) 12 (20.0) 9 (14.5) 15 (23.8) 13 (21.3) 15 (25.0) 13 (21.7) 3 (5.1) 12 (20.3) 9 (15.0) 16 (25.8) 117 (19.3) PI be o e ea men adminis a ion (baseline PI) VRS Mild n (%) 1 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.7) 0 (0.0) 1 (1.6) 3 (0.5) Mode a e n (%) 40 (66.7) 43 (69.4) 39 (61.9) 41 (67.2) 35 (58.3) 43 (71.7) 40 (67.8) 35 (59.3) 39 (65.0) 33 (53.2) 388 (64.0) Se e e n (%) 19 (31.7) 18 (29.0) 24 (38.1) 20 (32.8) 25 (41.7) 17 (28.3) 19 (32.2) 23 (39.0) 21 (35.0) 27 (43.5) 213 (35.1) Missing n (%) 0 (0.0) 1 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.6) 2 (0.3) VRS-PI measu ed on a 4-poin VRS (0 = ‘none’ o 3 = ‘se e e’). Baseline PI e e s o he VRS-PI eco ded immedia ely p io o he adminis a ion o he s udy medica ion (in con as o VRS-PI measu ed be o e andomisa ion o eligibili y pu poses). Baseline PI was mode a e o se e e in 601 pa ien s; i was epo ed as “mild”by 3 (0.5 %) pa ien s and esul s we e missing o 2 (0.3 %) pa ien s due o compila ion da a e o on he eDia y Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 7 o 13 o placebo (p< 0.01), wi h he highes sco es in he DKP25/TRAM75 g oup. The pe cen age o pa ien s wi h ‘good’ o ‘excellen ’PGE esponse was 79 % in he DKP25/ TRAM75 g oup e sus 11 % in he placebo g oup. The pe cen age o pa ien s wi h ‘ e y good’and ‘excellen ’PGE was 51 % in he DKP25/TRAM75 g oup e sus 4.8 % in he placebo g oup. The analysis o dose– esponse ela ionship be ween he es ed s udy d ugs and he ac i e con ol showed ha DKP25/TRAM75 was he only combina ion ha was signi ican ly supe io o ibup o en 400 mg (p= 0.0028). Sa e y esul s O 611 pa ien s ea ed, 40 (6.5 %) epo ed a o al o 63 ad e se eac ions (ADRs), he mos equen being omi ing (21 pa ien s; 3.4 %), nausea (14 pa ien s; 2.3 %), dizziness (11 pa ien s; 1.8 %) and somnolence (5 pa ien s; 0.8 %) (Table 3). Apa om one case o “se e e”somno- lence in he DKP12.5/TRAM75 g oup (1.6 %), all ADRs we e conside ed “mild”(45 ADRs, 71 %) o “mode a e” (17 ADRs, 27 %) in in ensi y. Only one se ious ad e se e en (SAE) was epo ed in one pa ien (alloca ed o he TRAM75 g oup), consis ing in dizziness o mild in ensi y, which equi ed hospi aliza ion o moni o ing and esol ed spon aneously. The e en was assessed as “possibly ela ed” o he s udy medica ion. Dizziness is a commonly epo ed ADR associa ed o he use o amadol, occu ing in mo e han 10 % o pa ien s, acco ding o he au ho ized Summa y o P oduc Cha ac e is ics. Fig. 2 NNT o ≥50 % max TOTPAR compa ed wi h placebo o e six hou s pos dose. Maximum TOTPAR co esponds o he heo e ical maximum possible ime-weigh ed sum o he PAR sco es, measu ed on a 5-poin VRS (0 = ‘none’ o 4 = ‘comple e’). Ba s show 95 % con idence in e al o NNT, wi h colou change as poin es ima e (No e ha TRAM37.5 was no signi ican ly be e han placebo) Fig. 1 Pe cen age o pa ien s showing esponse (≥50 % max TOTPAR) o e 6 h pos -dose (P ima y Endpoin ). Maximum TOTPAR co esponds o he heo e ical maximum possible ime-weigh ed sum o he PAR sco es, measu ed on a 5-poin VRS (0 = ‘none’ o 4 = ‘comple e’) Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 8 o 13 The highes incidence o ADRs was epo ed in he TRAM75 g oup (17 %). This incidence was highe han epo ed in g oups ecei ing amadol 75 mg in combina ion (i.e. DKP12.5/TRAM75 and DKP25/ TRAM75) o which he incidence was o 9.5 % and 12 % o pa ien s, espec i ely. No dea hs o o he signi ican AEs occu ed. No pa ien discon inued because o AEs. The e we e no clinically ele an changes in he VS, physical examina ion, 12-lead ECG o labo a o y sa e y es s e sus baseline. O e all, all ea men s we e sa e and well ole a ed, wi h all DKP/TRAM combina ions p esen ing a sa e y and Fig. 4 Cumula i e equency (Kaplan-Meie es ima ion) o RM in ake (0–24 h) Fig. 3 Time cou se o mean PAR sco es (0–24 h). PAR measu ed on a 5-poin VRS (0 = ‘none’ o 4 = ‘comple e’) Moo e e al. The Jou nal o Headache and Pain (2015) 16:60 Page 9 o 13