Relief of acute low back pain with diclofenac-k 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial

Transcription

1 In ter na tional Jour nal of Clin i cal Phar ma col ogy and Ther a peu tics, Vol. 41 No. 9/2003 ( ) ORIGINAL Relief of acute low back pain with diclofenac-k 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial R.L. Dreiser 1, M. Marty 2, E. Ionescu 3, M. Gold 4 and J.H. Liu 4 1 Paris, France, 2 Clinica & Statistica, Issy les Moulineaux, France, 3 Novartis Consumer Health SA, Nyon, Switzerland, and 4 Novartis Consumer Health Inc., Parsippany, NJ, USA Diclofenac-K in acute low back pain Key words acute low back pain diclofenac-k 12.5 mg ef fi cacy flex i ble dos - age reg i men nonsteroidal anti-inflam - matory drugs Abbreviations N = num ber, Mean (SD) = mean (stan dard de vi a - tion), TOTPAR-x = to tal pain re lief over the first x hours area un der the pain re lief vs time curve from 0 x hours, SPID = sum mary of pain in ten - sity dif fer ences area un der the PID vs time curve from 0 x hours, VAS = vi sual an a logue scale, NSAIDs = non- ste - roidal, anti-in flam matory drugs, OTC = over- thecounter, non- prescrip - tive, ICH-GCP = In ter na - tional Con fer ence on Har mo ni za tion Good Clin i cal Prac tice, FD = first dose, FMD = flex i ble mul ti ple dose, ITT = intent- to-treat, ANOVA = analysis of variance, PID = pain in ten sity dif fer - ence, AE = ad verse event Re ceived Oc to ber 22, 2002; ac cepted April 26, 2003 Cor re spon dence to R.L. Drei ser, MD, PhD Pri vate prac tice, 7, rue Pi erre Haret, Paris, France drei ser@club-internet.fr Ab stract. Objective: To as sess ef fi cacy and safety of diclofenac-k 12.5 mg tab lets in the treat ment of acute low back pain (low back pain). Material/method: A mul ti ple dose, dou ble-blind, dou ble-dummy, ran dom - ized, pla cebo-controlled, par al lel group trial com pared diclofenac-k (12.5 mg; n = 124) with ibuprofen (200 mg; n = 122) and pla cebo (n = 126) in pa tients with mod er ate-to-severe acute low back pain. The treat ment con sisted of an ini tial dose of 2 tab lets fol lowed by 1 or 2 tab lets ev ery 4 6 hours as needed (max i - mum 6 tab lets/day) for 7 days. The pri mary ef fi cacy out come for the ini tial dose was TOTPAR-3, the summed to tal pain re lief over the first 3 hours. Sec ond ary ini tial dose out - comes in cluded TOTPAR-6, summed pain in - tensity differences SPID-3 and SPID-6, time to rescue medication or remedicate, and the End of First Dose global ef fi cacy as sess ment. The pri mary ef fi cacy out come for the flex i ble mul ti ple dos ing reg i men was the End of Study global efficacy assessment. Secondary out comes for mul ti ple dos ing in cluded time to res cue med i ca tion over the en tire study, the End of Day global ef fi cacy as sess ments (daily over Days 1 7), pain in ten sity dif fer - ences on the VAS mea sured at Visit 2 and 3, and change in Eifel algofunctional in dex. Safety/tolerability was as sessed by re cord ing adverse events. Results: Diclofenac- K 12.5 mg dem on strated su pe ri or ity vs pla cebo on the primary efficacy parameter and almost all sec ond ary ini tial dose out comes. With re spect to the ini tial dose, diclofenac-k 12.5 mg was also sig nif i cantly su pe rior to ibuprofen 200 mg on SPID-3. Ibuprofen 200 mg was su pe - rior to pla cebo only on the End of First Dose global efficacy assessment. The flexible mul - ti ple dos ing reg i mens of diclo fenac-k and ibu profen were both sig nif i cantly su pe rior to pla cebo on the End of Study global ef fi cacy assessment, time to rescue medication over the en tire study pe riod, the End of Day global ef fi cacy as sess ment on Days 1 2, pain in ten - sity dif fer ence on the VAS at Visit 3 and the Eifel algofunctional in dex at Visit 3 (also at Visit 2 in diclofenac-k 12.5 mg group). Both ac tive treat ments were as well tol er ated as placebo. Con clu sions: The flexible multiple dos ing reg i men of diclofenac-k 12.5 mg (ini - tial dose of 2 tab lets fol lowed by 1 2 tab lets ev ery 4 6 hours, max. 75 mg/day) is an ef - fec tive and safe treat ment of acute low back pain. Introduction Acute low back pain is a self-limited con - di tion de fined as a sud den at tack of pain in the lumbosacral re gion. Phys i cal signs are usu - ally lim ited to paravertebral mus cle spasm, ten der ness, and re stricted lower back mo tion with out ev i dence of nerve root in volve ment [Howell 1988]. Acute low back pain is one of the most com mon ail ments seen in the of fice prac tice. The an nual in ci dence of lum bar pain in France and North ern Amer ica is 5 10%, and the life time prev a lence ranges from 60 90% [Coste et al. 1994, Frymoyer 1988, Howell 1988, Gepner et al. 1994]. The ma jor - ity of pa tients with acute symp toms re quire a non-specific short- term treat ment that may include bed rest, analgesic medications, exer - cise and education [Frymoyer 1988, Gepner et al. 1994]. The goal of ther apy is to re lieve pain as quickly as pos si ble to im prove func - tional sta tus. Non-steroidal anti-inflammatory drugs (NSAIDs) seem to be particularly appropriate for the short-term symp tom atic re lief of mod - er ate-to-severe pain dur ing the acute phase

2 Dreiser, Marty, Ionescu et al. 376 for which of ten no spe cific caus ative le sion can be iden ti fied [Anon 1994a, van Tulder et al. 2000]. The guide lines of the Agency for Health Care, Pol icy and Re search state that NSAIDs al le vi ate acute low back pain by de - creas ing pain and pre sum ably by re duc ing in - flam ma tion and stiff ness, there fore, pro mot - ing heal ing [Anon 1994b]. A re cent Cochrane re view of NSAIDs for low back pain [van Tulder et al. 2000] draws a sim i lar con clu sion that NSAIDs are ef fec tive for short-term symp tom atic re lief in pa tients with acute low back pain. Diclofenac, as en teric-coated tab lets of diclofenac so dium Voltarol [Matsumo et al. 1991] or as res in ate cap sules [Bakshi et al. 1994], has been dem on strated to re lieve acute low back pain when ad min is tered at high doses of 150 mg per day. More over, diclo - fenac po tas sium (diclofenac-k Cataflam or Voltaren Rapid, dif fer ent prod uct names de - pend ing on coun try), a sugar-coated imme - diate re lease tab let, with usual dos age of mg per day (max. 200 mg when nec - es sary) is used for acute treat ment of pain ful syn dromes of the ver te bral col umn and non-articular rheu ma tism. A new im me di ate-release film-coated tab - let con tain ing 12.5 mg of diclofenac-k has been de vel oped. A flex i ble dos age reg i men is pro posed start ing with an ini tial dose of 2 tab - lets ( mg) fol lowed by 1 2 tab lets, 4 6 hourly as needed, to a max i mum daily dose of 75 mg for up to 5 days for pain. This flexible dosage regimen matches the existing OTC dose reg i men of other an al ge sics such as ibuprofen, al low ing the pa tient to ad just the treat ment ac cord ing to the se ver ity and du ra - tion of the symp toms. The pur pose of this trial was to dem on - strate the ef fi cacy and safety of diclofenac-k 12.5 mg tab lets used for 7 days in a flex i ble mul ti ple dos ing reg i men ver sus pla cebo and ibuprofen 200 mg to re lieve moderate- tosevere acute low back pain. Methods Study protocol This was a mul ti ple-dose, multicenter (54 centers), dou ble-blind, dou ble-dummy, ran domized, par al lel group trial, per formed in ac cor dance with the Dec la ra tion of Hel - sinki, In ter na tional Con fer ence on Har mo ni - zation Good Clin i cal Prac tice (ICH-GCP) stan dard and the na tional re quire ments to con duct clin i cal tri als in France. An Eth i cal Re view Board ap proved the pro to col, and all pa tients pro vided a writ ten in formed con sent be fore en rol ment. Inclusion and exclusion criteria A to tal of 372 adult pa tients (18 60 years of age) with un treated acute low back pain and on set within 2 days were en rolled in the study. Pain was at least mod er ate ( 50 mm) on a 100-mm vi sual an a logue scale (VAS) and on a 4-point pain in ten sity scale; not due to an associated radiculalgia, i.e. Lasègue sign ab sent or su pe rior to 90º; not ra di at ing be low the gluteal fold. Pain was in ter mit tent or con stant and ag gra vated by me chan i cal factors. Pa tients were ex cluded for known hy per - sen si tiv ity to diclofenac, ibuprofen, para - cetamol or as pi rin; cur rent dis ease sta tus that could in ter fere with safety or ef fi cacy of study med i ca tion; drug or al co hol abuse; re - quired an ti co ag u lant ther apy; preg nant or nurs ing; re quired hos pi tal iza tion or other treat ments for the back pain; pres ence of neu - ro logic symp toms; pre vi ous ep i sode of back pain within 3 months; pres ence of in flam ma - tory, infective, neoplastic, metabolic or struc - tural cause for back pain; chronic low back pain; symptomatic lumbalgia of vis ceral or i - gin; his tory of chemonucleolysis or spi nal cord sur gery. The fol low ing pre vi ous and con com i tant treat ments were not al lowed: chronic treat - ment with topical or systemic analgesics, corticosteroids (oral or in jec tions), anti-in - flam matory drugs, tran quil iz ers or mus cle relaxants; lo cal ste roid in jec tion for other pa - thol o gies within 30 days; benzodiazepinetype anxiolytics with analgesic or muscle re - lax ant ef fect or hypnotics un less started at least 6 months ear lier and main tained at a con - stant dose through out the trial; pre vi ous and con com i tant use of phys i cal or al ter na tive ther a pies to treat this ep i sode, e.g. ex er cise, kinesitherapy, chiropractic, acu punc ture, ho - me op a thy or phys io ther apy. Pre vi ous in take of an oral an al ge sic to treat this ep i sode or (at

3 Diclofenac-K in acute low back pain 377 the most) one ap pli ca tion of a top i cal NSAID, counter-irritant or mephenasin was per mit - ted, but re quired at least a 6-hour wash out. Dur ing the study the ap pli ca tion of heat and cold was not per mit ted. Sup port belts were not per mit ted ex cept for Dr. Gibaud s belt. Resting was al lowed, whether com plete bed rest or home rest with daily ac tiv i ties in - cluded, and the du ra tion of rest and dates were re corded in the di ary. Study medication The diclofenac-k 12.5 mg and ibuprofen 200 mg tab lets dif fered in shape and size; there fore blind ing was achieved with a dou - ble-dummy ap proach. A randomization sched ule was gen er ated by the study spon sor with pa tients ran dom ized in blocks of 3. Each pack age of study med i ca tion was la beled with a randomization num ber and blocks of con - secutively numbered packages were distrib - uted to each site. Sealed de cod ing en ve lopes were sup plied to the sites to al low unblinding of study med i ca tion in an emer gency, but all of these were ul ti mately re turned un opened to the study spon sor. When a pa tient qual i fied for randomization at a study site, the pa tient was as signed the pack age with the low est randomization num ber avail able in the cen ter at that time. El i gi ble pa tients were ran dom - ized to the 3 treat ment groups: diclofenac-k 12.5 mg, ibuprofen 200 mg, or pla cebo. The treat ment con sisted of an ini tial dose of 2 tab - lets (diclofenac mg, ibuprofen mg or pla cebo). Af ter the ini tial dose of the study med i ca tion, the pa tients were in - structed to take doses of 1 or 2 tab lets of the study med i ca tion ev ery 4 6 hours, not ex - ceed ing 6 tab lets per day (i.e. 75 mg diclofenac-k or 1,200 mg ibuprofen daily) for 7 days. The time of each dose and num ber of tab lets was re corded in the study di ary. Daily use of study med i ca tion was recorded in the pa tient di ary as well as by count ing the study med i ca tion left at the end of the trial. The res cue med i ca tion con sisted of 1 or 2 tab lets of paracetamol (500 mg per tab let) taken only in case of mod er ate-to-severe pain, not ear lier than 2 hours af ter the ini tial dose of study med i ca tion. The use of res cue medication terminated the participation of the pa tient in the trial. Efficacy assessments Be fore tak ing the ini tial dose, pa tients rated pain in ten sity on a 4-point cat e gor i cal scale (no pain, mild, mod er ate and se vere) and on a 100-mm VAS (no pain, un bear able pain) and com pleted the Eifel algofunctional ques tion naire which is the French val i dated ver sion of the Roland-Morris Back Pain Ques tion naire; val ues range be tween 0 (no) and 24 (max i mal dis abil ity) [Coste et al. 1993, Roland and Mor ris 1983]. Qual ifying pa tients took the ini tial dose and rated pain in - ten sity on the 4-point scale and pain re lief on a 5-point scale (no re lief, a lit tle, some, a lot, com plete re lief) at 30 min utes and 1, 2, 3, 4, 5 and 6 hours. Af ter 6 hours, or at time of res cue med i ca tion or remedication if ear lier, pa tients pro vided an End of First Dose (FD) global as - sess ment of ef fi cacy on a 5-point scale (poor, fair, good, very good, ex cel lent). Patients receiveded medication according to a flex i ble dos ing reg i men, for up to 7 days. An End of Day global ef fi cacy as sess ment on a 5- point scale was pro vided on any day the pa - tient re ceived res cue or con tin ued medica tion. The pa tient pro vided an End of Study global ef fi cacy as sess ment on the 5-point pain re lief scale when the study was com pleted at the end of Day 7 or when dis con tinu ing ear lier for any reason. Patients who used rescue medication re corded the time in the di ary. Pa tients re turned to the study site on Day 3 (Visit 2) and again on Day 8 or when dis con - tinu ing, if ear lier (Visit 3). At these vis its the di a ries were checked for com pli ance and use of con com i tant med i ca tions and oc cur rences of adverse experiences were recorded. The pa tient as sessed pain in ten sity on a 100-mm VAS and com pleted the Eifel algo functional ques tion naire. Statistical methods The pri mary hy poth e sis to be tested in the trial was that a low dose of diclofenac-k would be su pe rior to pla cebo to treat low back pain. An ad di tional hy poth e sis to be tested was that a low dose of diclofenac-k would be at least as good as a low dose of ibuprofen in this in di ca - tion. All tests were 2-sided at the α = 0.05 level. No adjustment for multiple comparisons was ap plied since the pri mary com par i son was

4 Dreiser, Marty, Ionescu et al. 378 diclofenac-k vs pla cebo. The pri mary pop u la - tion for ef fi cacy anal y sis was the intent-totreat (ITT) efficacy population. The FD (first dose) and FMD (flex i ble mul ti ple dose) ITT ef fi cacy pop u la tions in - cluded all treated sub jects who pro vided re - sults for any FD and FMD ef fi cacy out comes, re spec tively. The out comes mea sured at the study site vis its were ana lyzed in the pop u la - tion of all sub jects who at tended the vis its. Pain re lief was sum ma rized over the 6 hours fol low ing the first dose as TOTPAR-3 and TOTPAR-6. TOTPAR-3 was com puted as the area un der the curve of the pain re lief scores plot ted vs time over the first 3 hours, and TOTPAR-6 was com puted in cor re - spond ing fash ion. The pain in ten sity scores were trans formed to PIDs (pain in ten sity dif - fer ences), de fined at Hour X as the base line score mi nus the pain in ten sity score at Hour X. Pain in ten sity was then sum ma rized in similar fashion as SPID-3 and SPID-6. SPID-3 was com puted as the area un der the curve of the PID scores plot ted vs time over the first 3 hours, and SPID-6 was com puted in cor re spond ing fash ion. TOTPAR-3 was spec i fied in the pro to col as the pri mary FD ef fi cacy pa ram e ter and the End of Study global ef fi cacy as sess ment as the primary FMD efficacy parameter. ANOVA with main ef fects of treat ment and center and treatment-by-center interaction was used to com pare TOTPAR-3, TOTPAR-6, SPID-3, SPID-6 and End of Study global ef fi - cacy as sess ment. The ANOVAs for SPID-3 and SPID-6 also in cluded base line pain in ten - sity as a co-variate. Of the 23 small est cen ters, which ran dom ized a to tal of 73 pa tients, 12 cen ters did not ran dom ize at least 1 pa tient to each treat ment group. In the other 11 cen ters, be cause some pa tients did not pro vide all re - quested as sess ments, there was at least 1 time - point and 1 treat ment group for which no as - sess ments were pro vided. To per mit in- depth ANOVA anal y sis of the TOTPAR, SPID and global as sess ment re sults, it was there fore nec - es sary to col lapse these 23 cen ters into 10 pooled cen ters. One cen ter with 12 pa tients had no ibuprofen pa tient who pro vided as sess - ments of pain in ten sity or pain re lief at 6 hours. This cen ter was pooled with a 1-patient cen ter (ran dom ized to ibuprofen) in which the miss - ing in for ma tion was avail able. The other 21 cen ters were pooled, mostly in pairs, to pro - vide 9 cen ters each hav ing 5 8 pa tients and at least 1 pa tient ran dom ized to each treat ment group and at least 1 pa tient in each treat ment group pro vid ing an as sess ment at each time - point. ANOVA was also used for the changes from base line in both pain in ten sity on the 100-mm VAS and Eifel algofunctional scores with main ef fects of treat ment and cen ter, treatment-by-center interaction and baseline val ues as co-variates. For time to res cue med i ca tion or re - medication within 6 hours af ter the first dose and time to res cue med i ca tion over the en tire study pe riod, groups were com pared with the log rank test strat i fied by cen ter. The End of First Dose global ef fi cacy as sess ment and the End of Day global ef fi cacy as sess ments were ana lyzed with the Cochran-Mantel-Haenszel test of treat ment mean ridits strat i fied by cen - ter. Small cen ters were not pooled for any anal y ses other than the ANOVAs for SPID, TOTPAR and End of Study global ef fi cacy as sess ment as dis cussed above. Sample size determination power analysis The sam ple size was de ter mined with re - gard to the primary efficacy parameters based on re sults of an un pub lished mul ti ple-dose den tal pain trial of the study med i ca tion that assessed efficacy with similar procedures, since no lit er a ture for low back pain us ing the same ap proach was avail able. For TOTPAR-3, a stan dard ANOVA power cal cu - la tion showed that 100 pa tients per treat ment group would pro vide 80% power to de tect a 40% dif fer ence be tween the mean TOTPAR-3 of 2 treat ments (de fined as the difference between the TOTPAR-3 val ues di - vided by the mean of both TOTPAR-3). For the End of Study global ef fi cacy as sess ment, 100 pa tients per treat ment group were found to pro vide 80% power to de tect a 20% dif fer - ence be tween the mean rat ings. Results Study population The study was con ducted at 54 clin ics of general practitioners in France, between Jan -

5 Diclofenac-K in acute low back pain 379 Ta ble 1. Sub ject de mo graph ics and base line char ac ter is tics. Diclofenac-K Ibuprofen Pla cebo Ran dom ized (N) ITT-population FD (N) ITT-population FMD (N) Fe male N (%) 64 (51.6) 58 (47.5) 65 (52.8) Male N (%) 60 (48.4) 64 (52.5) 58 (47.2) Age years (mean (SD)) 40.9 (10.9) 40.6 (11.6) 41.0 (11.3) Cau ca sian N (%) 116 (93.5) 113 (92.6) 113 (91.9) With his tory of other low back pain N (%) 54 (43.5) 50 (41.0) 46 (37.4) On set within 48 h N (%) 119 (96) 120 (98.3) 122 (100) Base line pa ram e ters Se vere base line pain N (%) 73 (58.9) 65 (54.2) 57 (46.3) Mod er ate base line pain N (%) 51 (41.1) 55 (45.8) 66 (53.7) Pain in ten sity* (VAS, mean (SD)) 72.1 (10.9) 71.7 (11.3) 71.4 (10.1) Eifel algofunctional index* 13.6 (4.2) 13.3 (4.3) 13.0 (4.3) (mean (SD)) FD = ITT pop u la tion for first dose ef fi cacy; FMD = ITT pop u la tion for flex i ble mul - ti ple dose ef fi cacy. All sum mary sta tis tics above are com puted from the first dose ITT ef fi cacy pop u la tion. *Pain in ten sity VAS ranges from 0 = No pain to 100 = Un bear able pain; Eifel in dex ranges from A per pro to col anal y sis was not done, be cause there were very few vi o la tors in this study. u ary 1998 and Feb ru ary These clin ics ran dom ized 372 pa tients, with 16 clin ics ran - dom iz ing 1 3 pa tients apiece, 17 clinics ran - dom iz ing 4 6 pa tients apiece, 16 clin ics 7 12 patients apiece and 5 clin ics ran dom iz ing 18 pa tients apiece. Of these, 369 pa tients were in the FD ITT ef fi cacy anal y sis (Ta ble 1). Of the other 3 pa tients, 2 pla cebo pa tients pro vided no post-baseline ef fi cacy as sess ments and 1 pa tient was ran dom ized twice; the sec ond ran dom iza tion (to pla cebo) was ex cluded from the FD pop u la tion. All FD ITT pa tients were in the FMD ITT ef fi cacy pop u la tion ex - cept for 1 pa tient who dis con tin ued af ter the first dose as an early cure. The study pop u la tion was evenly split on gen der and over 90% were Cau ca sian. Mean age was ap prox i mately 40 years. More than 95% of pa tients had on set of the cur rent ep i - sode within 48 hours (60% oc curred within 24 hours). Re gard less of the method used to mea sure pain in ten sity at base line, the mean pain in ten sity was nearly iden ti cal in the 3 Fig ure 1. Flow of par tic i pants through each stage.

6 Dreiser, Marty, Ionescu et al. 380 groups. Base line mean scores on the Eifel algofunctional in dex ranged be tween 13 and 14, out of a max i mum score of 24. Dif fer - ences be tween treat ment groups on these de - mographic and baseline characteristics were not statistically significant. An overview of the flow of par tic i pants through each stage of the study is shown in Figure 1. Active drug usage patterns Fig ure 2. Mean pro file of first dose timed pain re lief as sess ments. Ta ble 2. Sum mary of first dose ef fi cacy re sults. Diclofenac-K 25 mg Ibuprofen 400 mg Pla cebo N Pain re lief at 3 h N (%) = None 25 (21.4) 21 (18.8) 32 (27.1) 1 = A little 26 (22.2) 35 (31.3) 44 (37.3) 2 = Some 36 (30.8) 37 (33.3) 31 (26.3) 3 = A lot 27 (23.1) 18 (16.1) 7 ( 5.9) 4 = Com plete 3 (2.6) 1 (0.9) 4 (3.4) Mean (SD) 1.6 (1.1) (1.1) 1.2 (1.0) TOTPAR (2.7) (2.5) 2.6 (2.3) SPID (1.7) 1, (1.6) 0.9 (1.4) N Mean (SD) TOTPAR (5.5) (5.0) 6.2 (4.9) SPID (3.7) (3.5) 2.3 (3.0) End of first dose ef fi cacy N (%) = Poor 35 (28.2) 37 (31.1) 56 (46.3) 1 = Fair 48 (38.7) 48 (40.3) 43 (35.5) 2 = Good 20 (16.1) 28 (23.5) 16 (13.2) 3 = Very good 16 (12.9) 6 (5.0) 4 (3.3) 4 = Ex cel lent 5 (4.0) 0 2 (1.7) Mean (SD) 1.3 (1.1) (0.9) (0.9) Time to res cue med i ca tion or remedication (me dian): h : min 4 : 44 4 : 50 4 : 50 Compared to pla cebo: 1 p < 0.05; 2 p < 0.01; 3 p < 0.001; 4 p = 0.03 Compared to ibuprofen: 5 p = 0.04 The av er age pa tient in the diclofenac-k 12.5 mg group used 19.3 tab lets over the course of the study on an av er age of 15.3 med i cat ing oc ca sions. A 1-tablet dose was taken on an av er age of ap prox i mately 11 (74%) of these oc ca sions. This com pares to 20.9 tab lets in the ibuprofen 200 mg group taken on an av er age of 15.6 med i cat ing oc ca - sions. A 1-tablet dose was taken on an av er - age of over 10 (67%) of these oc ca sions. In all, pa tients used roughly half of the 42 tab lets of ac tive med i ca tion they were given to cover a 7-day treat ment pe riod at the max i mum dose of 6 tab lets/day. In ei ther ac tive treat - ment group, over 90% of pa tients used study med i ca tion on both Days 1 and 2 and av er - aged just over 4 tab lets per day. On Day 1 this was pri mar ily 2-tablet doses and on Day 2 it was pri mar ily 1-tablet doses. Note that this was well be low the max i mum dose of 6 tab - lets per day. The num ber of pa tients med i cat - ing de creased there af ter un til about 50% of pa tients in ei ther ac tive treat ment groups were still us ing an av er age of about 3 tab lets on Day 7, mostly as 1-tablet doses. On most days, the mean num ber of tab lets taken and the mean num ber of 2-tablet doses were slightly greater in the ibuprofen 200 mg group than in the diclo fenac-k 12.5 mg group. First dose (FD) efficacy The time course for pain re lief af ter the first dose of 2 tab lets is shown in Fig ure 2. Other first dose out comes are shown in Table 2. A re sult on TOTPAR-3, the pri mary FD ef fi cacy out come, was pro vided by 356 (96.5%) of the 369 pa tients in the FD ITT ef fi - cacy pop u la tion. The other 13 pa tients (4 diclofenac-k, 4 ibuprofen and 5 pla cebo)

7 Diclofenac-K in acute low back pain 381 Ta ble 3. Sum mary of flex i ble mul ti ple dose ef fi cacy re sults (di ary data). Diclofenac-K Ibuprofen Pla cebo End of study N (%) = No re lief 15 (12.6) 16 (13.4) 32 (27.1) 1 = A lit tle 16 (13.4) 14 (11.8) 17 (14.4) 2 = Some 35 (29.4) 41 (34.5) 37 (31.4) 3 = A lot 31 (26.1) 35 (29.4) 19 (16.1) 4 = Com plete 22 (18.5) 13 (10.9) 13 (11.0) Mean (SD) 2.2 (1.3) (1.2) (1.3) Time to res cue med i ca tion N (%) h 5 (4.0) 5 (4.1) 7 (5.7) h 7 (5.6) 2 (1.6) 6 (4.9) > 48 h 7 (5.6) 9 (7.4) 20 (16.4) To tal res cued 19 (15.3) 2 16 (13.1) 2 33 (27.0) Daily global ef fi cacy as sess ment Day 1 N (%) = Poor 29 (23.4) 30 (24.8) 49 (40.5) 1 = Fair 51 (41.1) 48 (39.7) 47 (38.8) 2 = Good 23 (18.5) 35 (28.9) 21 (17.4) 3 = Very good 17 (13.7) 7 (5.8) 3 (2.5) 4 = Ex cel lent 4 (3.2) 1 (0.8) 1 (0.8) Mean (SD) 1.3 (1.1) (0.9) (0.9) Day 2 N (%) = Poor 20 (17.4) 19 (16.8) 39 (34.5) 1 = Fair 34 (29.6) 41 (36.3) 35 (31.0) 2 = Good 39 (33.9) 41 (36.3) 33 (29.2) 3 = Very good 17 (14.8) 11 (9.7) 4 (3.5) 4 = Ex cel lent 5 (4.3) 1 (0.9) 2 (1.8) Mean (SD) 1.6 (1.1) (0.9) (1.0) Day 3 (N = 313) 1.8 (1.1) (0.9) 1.3 (1.0) Day 4 (N = 278) 2.1 (1.0) (0.9) 1.5 (1.0) Day 5 (N = 246) 2.2 (1.0) (0.9) 1.8 (1.0) Day 6 (N = 201) 2.3 (0.9) 2.1 (0.9) 2.0 (1.0) Day 7 (N = 169) 2.3 (0.8) (1.0) 2.0 (1.0) Compared to pla cebo: 1 p < 0.05; 2 p < 0.01; 3 p < Compared to ibuprofen: 4 p = 0.03 did not pro vide suf fi cient as sess ments of pain re lief over the first 3 hours to com pute a TOTPAR-3 value. The start ing dose of 2 tab - lets of diclofenac-k 12.5 mg was sta tis ti cally significantly superior to placebo on the primary initial dose efficacy outcome TOTPAR-3, as well as TOTPAR-6 (p < 0.05). This is driven by sig nif i cant su pe ri or ity vs pla cebo on pain re lief from Hour 2 through Hour 5. To al low greater in sight into the re lief pro vided by the ini tial dose, pain re lief scores at Hour 3, the timepoint of peak ef fi cacy (Fig ure 2) are pre - sented in greater de tail in Ta ble 2. Diclo - fenac-k was sig nif i cantly su pe rior to pla cebo (p < 0.01) whereas ibu profen did not quite achieve statistically significant separation from pla cebo (p = 0.06). Diclofenac-K 12.5 mg was also sig nif i - cantly su pe rior to pla cebo on SPID-3 and SPID-6 (p < 0.05). This is driven by sig nif i - cant su pe ri or ity vs pla cebo on the PIDs at Hours 2 and 4 (data not shown). In con trast, ibuprofen was not statistically significantly su pe rior to pla cebo on ei ther TOTPAR or SPID at 3 or at 6 hours, or on pain re lief or PIDs at any timepoint. Note that diclo fenac-k 12.5 mg was sig nif i cantly su pe rior to ibu - profen 200 mg on SPID-3 (p = 0.04). This was driven by su pe ri or ity to ibuprofen 200 mg on the PID score at Hour 2. For the End of FD global ef fi cacy as sess ment, both diclo - fenac-k and ibuprofen (p = 0.03) were sta tis - tically significantly superior to placebo (Ta - ble 2). The dif fer ence be tween ibuprofen and diclofenac-k was not statistically significant. The per cent age of pa tients rat ing diclo - fenac-k as Good, Very good or Ex cel - lent (33.1%) was nu mer i cally greater than in the ibuprofen group (28.6%) and al most twice the rate in the pla cebo group (18.2%). The me - dian time to res cue med i ca tion or remedication dur ing the first 6 hours af ter the first dose was slightly less than 5 hours in all 3 treat ment groups. Al though pa tients were al lowed to res - cue any time af ter 2 hours, most chose to remedicate 4 6 hours af ter dos ing. There were no significant differences between the treat ment groups on this out come. Flexible multiple dose (FMD) efficacy The FMD outcomes summarize efficacy over the en tire pe riod in which pa tients were us ing their study med i ca tion ac cord ing to the FMD reg i men. The End of Study global as - sess ment and time to res cue med i ca tion were single measures of the entire experience, whereas the End of Day ef fi cacy as sess ments sum ma rize ef fi cacy on a day-to-day ba sis over all days in which the pa tients were med i - cated. A re sult on the End of Study global ef fi - cacy as sess ment, the pri mary FMD ef fi cacy out come, was pro vided by 356 (96.7%) of the 368 pa tients in the FMD ITT ef fi cacy pop u la -

8 Dreiser, Marty, Ionescu et al. 382 Ta ble 4. Ef fi cacy out comes mea sured at study sites dur ing vis its: changes from base line. Diclofenac-K Ibuprofen Pla cebo VAS pain in ten sity dif fer ences mean and (SD) in mm N Visit (18.2) 28.6 (16.8) 25.4 (17.4) N Visit (26.1) (24.0) (26.9) Eifel in dex score change from base line, mean and (SD) N Visit (4.0) (3.9) 3.7 (4.0) N Visit (5.7) (5.2) (5.3) Compared to pla cebo: 1 p = 0.02, 3 p < tion. Of the other 12 pa tients (5 diclofenac-k, 3 ibuprofen and 4 pla cebo), 10 dis con tin ued pre ma turely; 5 for early cure (3 diclofenac-k, 1 ibuprofen and 1 pla cebo), 4 for un sat is fac - tory ther a peu tic ef fect (2 ibuprofen, 2 pla - cebo) and 1 diclofenac-k pa tient who with - drew con sent. Both ac tive treat ment groups were sta tis - tically significantly superior to placebo on the End of Study global ef fi cacy as sess ment (p < 0.01, Table 3), with al most 75% of pa - tients in ei ther ac tive group rat ing the over all re lief from low back pain as Some, A lot or Com plete com pared to 58.5% in the pla - cebo group. Pa tients in both ac tive groups were also statistically significantly less likely to use res cue med i ca tion (p < 0.01). Dif fer - ences be tween the ac tive groups on these out - comes were not statistically significant. For the End of Day global ef fi cacy as sess - ments, diclofenac-k was sig nif i cantly su pe - rior to pla cebo from Day 1 to Day 5, whereas the ibuprofen group was sig nif i cantly su pe - rior to pla cebo only on Days 1 and 2. Diclofenac-K was su pe rior to ibuprofen on Day 7 (p = 0.03) when 46% of sub jects con - tin ued to med i cate and pro vide as sess ments. On all other days the su pe ri or ity of diclo - fenac-k over ibuprofen ap proached but did not achieve statistical significance. Table 4 sum ma rizes the ef fi cacy out - comes mea sured at the study sites dur ing the vis its. There were sub stan tially fewer pa tients pro vid ing as sess ments at Visit 2 than at Visit 3 be cause some pa tients who dis con tin ued pre ma turely from the study for var i ous rea - sons (e.g. use of res cue med i ca tion, early cure or ad verse events) re turned to the site for only 1 fol low-up visit, which was clas si fied as Visit 3. Pa tients in both ac tive treat ment groups showed sig nif i cant im prove ment in pain in ten sity on VAS, i.e. about 11 mm com - pared to pla cebo (p < 0.001) at Visit 3. Both ac tive treat ment groups showed sim i lar su pe - ri or ity (p < 0.001) over pla cebo on the Eifel algofunctional score at Visit 3. Diclofenac-K was also sig nif i cantly su pe rior to pla cebo at Visit 2 (p = 0.02). Adverse experiences The per cent ages of pa tients re port ing ad - verse events were com pa ra ble in the diclo - fenac- K (12.9%) and ibuprofen (11.5%) treat ment groups and higher in pla cebo (15.9%). The most fre quent ad verse events were di ges tive such as di ar rhea (1 diclo - fenac- K, 4 ibuprofen and 5 pla cebo), nau sea (1 diclofenac, 2 pla cebo), hem or rhage rec tum (1 ibuprofen), ab dom i nal pain (3 diclofenac, 5 ibuprofen and 4 pla cebo), and vom it ing (2 ibuprofen and 1 pla cebo). The diclofenac group re ported 6 cases of ner vous sys tem re - ac tions (3 cases of som no lence) as com pared to 1 in ibuprofen and 5 in pla cebo. There were no se ri ous ad verse events and no deaths. 16 pa tients were dis con tin ued pre ma turely due to an ad verse event: 4 in diclofenac, 4 in ibuprofen and 8 in the pla cebo group. About 92% of pa tients in both diclofenac-k and ibuprofen groups eval u ated the study drug tolerability and safety as Good or Very good as com pared to only 85% in the pla - cebo group. Discussion This study ful fils the qual ity cri te ria for tri als in acute low back pain [Cochrane re - view van Tulder et al. 2000]: a randomized, dou ble-blind and dou ble-dummy de sign; pa - tients years of age; acute non-specific low back pain; ex clu sion of pa thol o gies such as in fec tion, neo plasm, me tas ta sis, os teo po - ro sis, rheu ma toid ar thri tis, or frac tures; use of a sec ond NSAID, i.e. ibuprofen, as an ac tive con trol. Out comes such as End of Study

9 Diclofenac-K in acute low back pain 383 global efficacy assessment, pain intensity on VAS and on nu mer i cal rat ing scale and backspecific functional status, i.e. Roland Dis abil - ity Ques tion naire in the French val i dated ver - sion (Eifel algofunctional score [Roland and Mor ris 1983, Coste et al. 1993]) were also used. This study con firms the ef fi cacy of NSAIDs for the man age ment of moderateto- severe pain dur ing the acute phase of low back pain [Anon 1994a, 1997]. In par tic u lar, this is the first study to dem on strate that a low dose of diclofenac-k 12.5 mg, in a flex i ble dose reg i men over 7 days, ef fec tively re lieves mo der ate-to-severe pain due to an acute low back pain ep i sode. A pre vi ous placebo- con - trolled study of in tra mus cu lar diclofenac cited in the Cochrane re view was at a daily dose of 150 mg [Babej-Dolle et al. 1994]. Ef fi cacy of the diclofenac-k 12.5 mg tab - let was es tab lished as early as the ini tial dose of 2 tablets, with significant separation of ac - tive from pla cebo on the as sess ment of pain re lief from 2 5 hours. The over all ben e fits of the 7-day flex i ble dos ing reg i men were dem - on strated in the sig nif i cantly greater over all amount of re lief re ported by the pa tients on the End of Study global ef fi cacy as sess ment. Also note wor thy was the 11 mm dif fer ence be tween diclofenac-k 12.5 mg and pla cebo on the spon ta ne ous pain in ten sity as sess ment on the 100-mm VAS that was per formed at the fi nal visit to the study site. This re sult ex ceeds the gen er ally ac cepted cri te rion of 10 mm for a clinically relevant difference. The ac tive con trol, ibuprofen 200 mg, a well-known OTC drug with a fa vor able safety pro file was also taken in a cor re spond ing flex i ble dos ing reg i men, and the trial sen si tiv - ity was tested. Pre vi ously it has been dem on - strated that ibuprofen 400 mg t.i.d. for 7 days leads to ab sence of acute low back pain pain or pain of mild se ver ity in 84% of treated pa - tients [Hosie 1993]. In our study, the only ev i - dence of first dose ef fi cacy of ibuprofen 400 mg was sig nif i cant su pe ri or ity over pla cebo on the End of First Dose global ef fi cacy as - sess ment. In con trast, the first dose of 2 tab - lets of diclofenac 12.5 mg was not only sig - nif i cantly su pe rior to pla cebo on nu mer ous first dose out comes but was also sig nif i cantly su pe rior to ibuprofen 400 mg on SPID-3. This was not at trib uted to a dif fer ence in pain in - tensity at baseline because differences at base line were quite small (Ta ble 1) and base - line pain in ten sity was ad justed as a co- vari - ate in the ANOVA model used for the test ing. Differences in outcomes associated with the flex i ble mul ti ple dos ing reg i men gen er ally fa vored diclofenac-k 12.5 mg only mod estly and without statistical significance compared to ibuprofen, and both ac tive treat ments were sig nif i cantly su pe rior to pla cebo on nu mer - ous out comes. The flex i ble dos age reg i men of up to 6 tab lets of diclofenac-k per day for 7 days can be con sid ered ad e quate given that on Day 7 only 60 (48%) of 124 randomized diclofenac pa tients used any study med i ca tion and that these 60 pa tients av er aged less than half (2.93 tablets) of the max i mum rec om mended daily dose. This cor re sponds as well to the expectations re gard ing acute low back pain in which spon ta ne ous re cov ery nor mally oc curs within 1 week [Coste et al. 1994]. In their daily global as sess ments of ef fi - cacy the patients typ i cally rated diclofenac 12.5 mg as Fair to good on Days 1 3 and Good to very good on Days 4 7 (Ta ble 3). Al though these rat ings are not par tic u larly im pres sive, it is also true that most pa tients did not use a sub stan tial part of the to tal daily dose al lowed un der the flex i ble dos ing reg i - men for ei ther ac tive med i ca tion. Even dur ing the first few days, only about a third of the pa - tients used more than 4 tab lets of ei ther ac tive study med i ca tion. Over the en tire week, the typ i cal pa tient used only half of the max i mum al lowed 42 tab lets. Af ter the first dose of 2 tab lets, most doses were of 1 tab let. Pa tients were not asked why they did not take more of the study med i ca tion to pro vide greater re lief of their back pain. How ever, the pat terns of use of ibuprofen were al most iden - ti cal, so the ten dency to un der-medicate does not ap pear to be re lated to a spe cific treat - ment. The issue of the clinical significance of the rat ings on the daily End of Day global ef fi - cacy as sess ments over the first few days also bears fur ther com ment. It is well-established that the symp toms of acute low back pain are dif fi cult to treat. The ef fi cacy of higher doses of NSAIDs has been de scribed in a metaanalytical re view as slightly ef fec tive for short-term global im prove ment of pa tients with acute low back pain [van Tulder et al. 2000]. None the less, NSAIDs are widely used

10 Dreiser, Marty, Ionescu et al. 384 to re lieve acute low back pain, re flect ing the fact that there are no readily avail able al ter na - tives that are clearly more ef fec tive. The stud - ies in the meta-analytic re view in gen eral did not con sider sin gle dose ef fi cacy but were focused in stead on over all ef fect af ter 1 2 weeks. The re view con sid ered a di chot o mous mea sure of global im prove ment from the stud ies that com pared an NSAID with pla - cebo and com puted a pooled rate ra tio (RR) of 1.20 to de scribe the like li hood of global im - prove ment on ac tive rel a tive to pla cebo. Such an anal y sis can be per formed on the End of Study global ef fi cacy as sess ment re - ported in Ta ble 3 if the 5 cat e go ries are dichotomized. If the re sponses of some, a lot and com plete re lief of acute low back pain can be col lapsed into the suc cess cat e - gory and none and a lit tle into the fail ure cat e gory, the RR for diclofenac rel a tive to pla cebo is 1.26 (i.e. 73.9%/58.5%), which com pares fa vor ably to the re sult of the metaanalytical re view. If the cat e gory some re - lief is des ig nated as a fail ure rather than a success, the RR in creases to This same anal y sis ap plied to the End of Day 1 and End of Day 2 global ef fi cacy as sess ments shown in Ta ble 3 yields RR re sults that are even more fa vor able to diclofenac. The con clu sion is there fore ro bust that in the con text of the ef fi - cacy of NSAIDs in gen eral to treat acute low back pain, the ef fi cacy pro vided by the flex i - ble dos ing reg i men of diclofenac-k 12.5 mg tablets is clinically relevant. In as sess ing the likely util ity of the flex i - ble mul ti ple dose reg i men of diclofenac-k 12.5 mg tab lets, a fur ther con sid er ation is im - por tant. In most stud ies of an al ge sics, a pa - tient is in structed to take a spe cific num ber of tab lets at spe cific times each day, for a spe - cific num ber of days. In this study, pa tients were given com plete free dom to take the study med i ca tion as they found fitting, within the minimal restrictions of the flexible dosing reg i men, un til they felt that it was no lon ger needed. There fore, the ef fi cacy re ported in this study is par tic u larly likely to re flect the efficacy that patients will experience when they use diclofenac-k 12.5 mg tab lets to treat acute low back pain un der con di tions of us - age in reality. The in ci dence of ad verse events, pre dom - i nantly gas tro in tes ti nal, was low and com pa - ra ble for the 3 treat ment groups. Fur ther more, the global as sess ments of the safety and tolerability of diclofenac-k and ibuprofen at the end of the trial were su pe rior to pla cebo. No se ri ous ad verse events were re ported. Since the gastrointestinal safety is doserelated [Gar cia-rodriguez and Hernandez- Diaz 2001], these data with diclofenac-k 12.5 mg con firm the ex cel lent ben e fit-risk ra - tio of low-dose NSAIDs for short- term treat - ment. In sum mary, this clin i cal trial con ducted ac cord ing to the high qual ity stan dards for tri - als of low back pain, shows ev i dence that the flex i ble dos age reg i men with diclofenac-k 12.5 mg is ef fec tive and at least com pa ra ble to ibuprofen 200 mg in treat ment of acute low back pain. This treat ment not only ef fec tively re lieved mod er ate-to-severe acute low back pain, but also sig nif i cantly de creased the dis - ability score. The flexible dosage regimen allows ad ap ta tion of the treat ment to symp tom in ten sity and mir rors the nor mal real-world us age of non-prescription an al ge sics. Acknowledgments This study was sup ported by Novartis Con sumer Health SA, Nyon, Switzerland. The fol low ing in ves ti ga tors par tic i pated in this study: L. Aïm, Pantin; P. Amar, Levallois- Perret; P. Angeli, Villejuif; J.L. Astar, Paris; C. Baranes, Paris; H. Belahcen, Paris; P. Benat, Paris; L. Benichou, Saint- Ouen; G. Biro, Montrouge; H. Boccara, Paris; L. Boujenah, Paris; M. Bres, Langeais; C. Caldagues, Paris; P. Carcaillon, Joinville le Pont; H. Chabanne, Charenton; E. Chabaud, Yvry-s/Seine; N. Cha pel, Joué-les- Tours; D. Cochet, Tours; A. Co hen, Saint- Ouen; G. Cosson, Champs sur Marne; P. Cusson, Blois; T. Debas, Ormesson s/marne; G. Delamare, Blois; G. Deraedt, Saint-Denis; S. Dumas, Villejuif; F. Dupont, Saint-Denis; C. Durazzi- Dureault, Paris; G. Forcada, Vincennes; J. Fridman, Paris; G. Garçon, Paris; P. Guerillot, Paris; A. Guillaumaud, Senlis; J.M. Halmen - schlager, Paris; A. Hamzaoui, Tours; M. Hindamian, Gentilly; M. Hoze, Vincennes; J.M. Huet, Villeneuve le Roi; M. Ja cob, Epernay; S. Kichelewski, Saint-Ouen; S. Labatide- Alanore, Paris; P. Lazeras, Torçy; C. Leclerc, Mai son-alfort; M. Lecuyer, Lognes; P. Leprince, Tours; R. Melka, Saint-

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