tolerability of Stilpane and Tramacet after third molar extraction

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1 Southern Africn Journl of Anesthesi nd Anlgesi 2015; 21(2): Open Access rticle distributed under the terms of the Cretive Commons License [CC BY-NC-ND 4.0] South Afr J Anesth Anlg ISSN EISSN The Author(s) RESEARCH tolerbility of Stilpne nd Trmcet fter third molr extrction *, JM Dippenr b, M Nell, M Royds c Deprtment of Phrmcology, University of Pretori, Pretori, South Afric b Deprtment of Mxillo Fcil Orl Surgery, Orl nd Dentl Hospitl, University of Pretori, Pretori, South Afric c CyteSpce, Pretori, South Afric *Corresponding uthor, emil: Bckground: sites of the nociceptive pthwy. Fixed-dose combintion nlgesics fcilitte reduction in dose of individul components, tolerbility of two widely prescribed combintion nlgesics, Stilpne (prcetmol/codeine/meprobmte) nd Trmcet (prcetmol/trmdol). Methods: A prospective rndomised prllel group phse IV clinicl tril ws conducted in 100 ptients experiencing moderte to severe pin fter third molr extrction t the Orl nd Dentl Hospitl, University of Pretori. Pin intensity nd pin relief nd Totl Pin Relief (TOTPAR) were clculted ccording to stndrd methods. Beck Anxiety Questionnire ssessed nxiety. Results: Conclusions: well-tolerted combintion nlgesics in ptients experiencing moderte to severe cute pin. Keywords: cute pin, nxiolytic, codeine, combintion nlgesics, meprobmte, prcetmol, Stilpne, Trmcet, trmdol Introduction Acute pin is disbling nd common, nd while it my be inevitble, 1 Aggressive control of cute pin my lso reduce the risk of developing chronic or even lifelong pin. 2 Successful tretment of moderte to severe cute pin often necessittes severl nlgesics the cuse of the pin s well s other ptient nd externl fctors, trditionl stepwise pproch includes commencing tretment (NSAID) nd therefter, co-prescribing wek opioid such s codeine or trmdol. 3 This rtionl prctice fcilittes dditive or the use of the more potent opioids. 4,5 The strong opioid-spring constiption, urinry retention, respirtory depression nd sedtion, which re importnt fctors prticulrly when considering pin ssocited with mbultory surgery nd the incresing need to fcilitte n erlier hospitl dischrge. 5 potentil dvntges over monotherpy which include reduction in dose of ech of the components, theoreticlly resulting in combintion nlgesics my lso be invluble in promoting complince. 6 For instnce, Stilpne, combintion nlgesic widely prescribed in South Afric contins reltively smll doses of respectively in cute pin mngement. 7,8 Low-dose meprobmte Pin is often ccompnied by nxiety, nd in the pst it ws therefore considered its nxiolytic properties. 9 Yet it ppers tht meprobmte lso possesses intrinsic nlgesic properties, which my further 10 Another populr South Africn combintion nlgesic, Trmcet, interction llows for substntil reduction in the usul individul dose. 11 Anlgesic superiority hs been demonstrted for this combintion compred to its individul components. 11 Of note is which re ssocited with gstric ulcertion nd hemorrhge, nd possibly dely in post-surgicl bone heling. 12 Opioids re preferred to NSAIDs in this context s well s in ptients with renl impirment, bleeding disorders, on nticogulnt therpy or who hve other contrindictions including pregnncy nd llergies. severe pin nd re often used interchngebly in South Afric However, their mechnisms of ction re somewht Stilpne nd Trmcet in n cute pin model. Removl of wisdom teeth (the four third molrs) is usully ccompnied by 16 Understndbly the procedure my lso cuse considerble distress to the ptient nd precipitte cute nxiety, prticulrly The pge number in the footer is not for bibliogrphic referencing

2 A rndomised clinicl tril compring the nlgesic nd nxiolytic efficcy nd tolerbility of Stilpne nd Trmcet fter third molr extrction 23 prior to surgery. 17 It is therefore useful model for the clinicl medicines. Methods Study design A prospective single-blind rndomised prllel group single centre phse IV clinicl tril ws conducted to compre the Trmcet using vlidted cute third molr extrction pin model. 18 The study ws pproved by the University of Pretori Reserch Ethics Committee (236/2112) nd ws registered with NHREC (DOH ). The Medicines Control Council ws lso Ptients were recruited from Februry 2013 November Study popultion One hundred eligible ptients presenting to the Orl nd Dentl Hospitl, University of Pretori, generlly in good helth ccording to the Americn Society of Anesthesiologists Scle (Stge I or II), outptient extrction of three or four impcted molrs, two of which were mndibulr thus requiring bone removl, with n nd hving given written informed consent, were selected to prticipte in the study. Ptients who were pregnnt or lctting, illiterte or dignosed with psychotic or bipolr disorders, those whose intke of lcohol exceeded 25 units week, those with serious crdiovsculr disese, brin injury or seizure disorders, nd those on concurrent opioids, cocine, stimulnts, ntidepressnts, ntipsychotics or nxiolytic mediction, were excluded from the study. Ptients who scored 2 (moderte) or 3 (severe) on the 4-point Likert scle for pin intensity 19 pin visul nlogue scle, 20 within 2 h post-surgery, were rndomised in block sizes of ten to one of the two tretment groups where they received either two Stilpne cpsules or two Trmcet tblets six hourly. Ptients were unwre of the tretment received nd identicl mediction bottles were coded nd pckged with study mediction ccording to the rndomistion sequence in order to mintin the blind. Rescue common to both preprtions, in order to limit the confounding potentil of dditionl drug drug interctions. In ccordnce with the Declrtion of Helsinki, the Europen Union Clinicl Trils Directive, the Food nd Drug Administrtion nd other Good Clinicl Prctice regultions, ptients hd the right to withdrw from the study without prejudicing their subsequent medicl cre. Ptients reported pin intensity on the 4-point Likert Scle, where 0 represented no pin, 1: mild pin, 2: moderte pin nd 3: severe pin, s soon s they were coherent post-surgery. 19 Ptients lso recorded their pin intensity on visul nlogue pin scle 20 (PAR) ws lso mesured t these time points using the 5-point Likert Scle where 0 denoted none, 1: little, 2: some, 3: lot nd 4: complete. 21 time to perceptible pin relief s well s meningful pin relief fter the dministrtion of the initil dose of nlgesic. The Beck Anxiety Questionnire which mesures cognitive nd somtic components of nxiety ws used to ssess ptients of 0 16 represented mild, 17 30: moderte, nd 31 nd bove: severe nxiety. 22 Tolerbility nd sfety Vitl signs including blood pressure, body weight, height, respirtion nd hert rtes were recorded before nd immeditely fter surgery, Any dverse chnges in ptient s medicl condition ws recorded s n dverse event. Ptients received diry crd to record dverse events t home nd the investigtor ctegorised these by their reltionship to study mediction, intensity nd seriousness. The outcome of the event ws lso recorded. Serious Adverse Events were reported to the University of Pretori s Ethics Sttisticl nlyses A smple size of t lest 26 ptients per group ws required for (ITT) nd per-protocol (PP) popultions, while sfety nlyses included rndomised ptients who took t lest one dose of study tretment. Continuous dt ws summrised using descriptive sttistics such s number of observtions (n), men, stndrd devition (SD), medin, minimum (min) nd mximum(mx). Ctegoricl dt ws presented s bsolute numbers (n) nd percentge (%). (PID) between bseline nd scheduled visits, nd hourly pin relief (PAR) t ech time point. The Summed Pin Intensity (SPRID) nd Totl Pin Relief (TOTPAR) were clculted ccording to stndrd methods. Anlysis of covrince (ANCOVA) ws used to nlyse SPID nd SPRID, the VAS nd the Beck Anxiety Scores. Anlysis of vrince (ANOVA) ws used to nlyse TOTPAR nd included tretment rms s fctors. Shpiro Wilk test ws used with corresponding p Results Demogrphic nd other bseline chrcteristics nd 48 in the Trmcet group) enrolled in nd completed the study. All were included in the sfety nd ITT popultions (Figure 1). The study popultion comprised more women thn groups ws similr (Tble 1) The pge number in the footer is not for bibliogrphic referencing

3 24 Southern Africn Journl of Anesthesi nd Anlgesi 2015; 21(2):22-27 Enrolment Assessed for eligibility (n = 103) Excluded (n = 3) Not meeting inclusion criteri (n = 3) Rndomised (n = 100) Alloction Allocted to Stilpne (n = 52) Received llocted intervention (n = 52) Did not receive llocted intervention (n = 0) Allocted to Trmcel (n = 48) Received llocted intervention (n = 48) Did not receive llocted intervention (n = 0) Follow-up Lost to follow-up (n = 0) Discontinued intervention (n = 0) Lost to follow-up (n = 0) Discontinued intervention (n = 0) Anlysis ITT Anlysis (n = 52) Excluded from nlysis (n = 0) ITT Anlysis (n = 48) Excluded from nlysis (n = 0 Figure 1: Consolidted Stndrds of Reporting Trils (CONSORT) flow digrm Tble 1: Demogrphic chrcteristics (gender nd rce) Vrible Ctegories Stilpne Cpsules N = 52 Trmcet Tblet N = 48 Overll N = 100 n (%) Gender Mle 17 (32.7) 20 (41.7) 37 (37.0) Femle 35 (67.3) 28 (58.3) 63 (63.0) Rce Cucsin 30 (57.7) 22 (45.8) 52 (52.0) Blck 19 (36.5) 24 (50.0) 43 (43.0) Asin 0 1 (2.1) 1 (1.0) Other 3 (5.8) 1 (2.1) 4 (4.0) moderte to severe cute pin ssocited with third molr (Tble 2) This ws corroborted by the results of the pin intensity ssessment by VAS (Tble 3) s well s totl pin relief (TOTPAR) (Tble 4), sum of hourly pin relief nd hourly pin intensity 5 groups. Furthermore, nlyses of secondry vribles including perceptible pin relief nd time tken for meningful pin relief were comprble between the two groups (dt not shown). good. At this time, 2% in both groups thought it ws poor, 4% in Tble 2: Stilpne cpsules N = 52 Trmcet tblet N = 48 Adjusted trmcet (95% CI) p-vlue 3.46 (1.64) 3.05 (2.12) 0.13 ( 0.76, 0.51) (14.10) 3.51 (20.05) 3.04 ( 9.97, 3.90) (48 ± 24 h) (36.36) (39.65) 7.45 ( 6.74, 21.65) (86.99) (91.57) 9.56 ( 21.58, 40.70) The pge number in the footer is not for bibliogrphic referencing

4 A rndomised clinicl tril compring the nlgesic nd nxiolytic efficcy nd tolerbility of Stilpne nd Trmcet fter third molr extrction 25 Tble 3: Visul nlogue pin scle (ITT popultion) Stilpne cpsules N=52 Trmcet tblet N=48 Adjusted Trmcet (95% CI) p-vlue (24.21) (23.28) 0.57 ( 8.92, 7.78) (27.67) (23.05) 1.34 ( 8.44, 11.12) (48 ± 24 h) (23.74) (15.95) 5.58 ( 1.01, 12.16) (20.59) (20.84) 0.63 ( 7.58, 6.32) Tble 4: Assessment of totl pin relief (TOTPAR) (ITT popultion) Stilpne Cpsules N = 52 Trmcet Tblet N = 48 Adjusted Trmcet (95% CI) p-vlue 5.58 (1.58) 5.54 (1.93) 0.04 ( 0.66, 0.73) (13.59) (19.22) 2.36 ( 8.92, 4.21) (48 ± 24 h) (44.06) (30.83) ( 26.65, 3.77) (96.35) (80.34) ( 52.45, 18.28) Tble 5: Stilpne cpsules N = 52 Trmcet tblet N = 48 Adjusted Trmcet (95% CI) p-vlue 2.45 (1.72) 2.82 (2.06) 0.01 ( 0.50, 0.52) (27.02) (38.69) 5.77 ( 19.12, 7.57) (48 ± 24 h) (43.10) (43.83) 2.70 ( 18.46, 13.07) (93.12) (78.64) 4.39 ( 30.91, 22.13) the Stilpne group nd 13% in the Trmcet group fir, 33% in the Stilpne group nd 38% in the Trmcet group good, nd 22% in the Stilpne group nd 10% in the Trmcet group In both tretment groups, pproximtely 70% of ptients chieved perceptible pin relief nd 35% of ptients chieved tretments (dt not shown). Tolerbility nd sfety signs nd physicl exmintions were within norml rnges. The most common tretment emergent events were nuse (Stilpne 9.6 %, Trmcet 12.5%), vomiting (Stilpne 5.8 %, Trmcet 6.3%), somnolence (Stilpne 15.4%, Trmcet 14.6%), dizziness (Stilpne 1.9 %, Trmcet 6.3%), hedche (Stilpne 1.9 %, Trmcet 2.1%), insomni (Stilpne 1.9%, Trmcet 2.1%), pruritus (Stilpne 5.8 %, Trmcet 2.1%) nd rsh (Stilpne 0 %, Trmcet 4.2%). No ptients discontinued tretment due to Anxiety ws ssessed prior to nd post-surgery, nd therefter, t or Trmcet. The shift in nxiety levels from bseline is outlined in Tble 6. More thn 90% of ptients in both tretment rms dose which ws lrgely sustined for the durtion of the study period. At 48 h, however, two ptients in the Trmcet group developed moderte nxiety, one of whom returned to stte of Trmcet group who initilly experienced moderte nxiety, group experienced moderte nxiety throughout the study tretment rms. Discussion severe pin. This study compred the nlgesic nd nxiolytic extrction, procedure commonly ssocited with substntil pin ensure tht ptients underwent similr degrees of surgery. The mximum chievble score of 16 took cognisnce of whether teeth were erupted nd whether impction involved soft tissue, prtil bone, complete bone or unusul impction such s horizontl/ inverted or posterior/nterior. 18 All ptients required bone removl for two mndibulr impcted molrs. Not surprisingly, ll enrolled ptients experienced moderte to severe post-opertive pin nd were therefore eligible for inclusion in the study The pge number in the footer is not for bibliogrphic referencing

5 26 Southern Africn Journl of Anesthesi nd Anlgesi 2015; 21(2):22-27 Tble 6: Shift in nxiety level (ITT popultion) Bseline Stilpne (N = 52) n (%) Trmcet (N = 48) n (%) Mild Moderte Severe Mild Moderte Severe Mild 49 (94.2) 3 (5.8) 0 46 (95.8) 2 (4.2) 0 Moderte Severe (48 ± 24 h) Mild 49 (94.2) 3 (5.8) 0 44 (91.7) 1 (2.1) 0 Moderte (4.2) 1 (2.1) 0 Severe Mild 49 (94.2) 3 (5.8) 0 45 (93.8) 1 (2.1) 0 Moderte (2.1) 1 (2.1) 0 Severe Stilpne nd Trmcet contin similr doses of prcetmol, in Stilpne, nd trmdol present in Trmcet re both pure 23 Trmdol lso increses synptic serotonin nd nordrenline levels, thereby cting on n dditionl site long the nociceptive pthwy. Nonetheless, per milligrm, codeine nd trmdol re considered to hve similr opioid nlgesic equivlence. 24 The nlgesic Trmcet in lleviting the moderte to severe cute pin contrsted with 10% of ptients in the Trmcet group. component, meprobmte. Although it hrbours nlgesic properties, it is unlikely tht low dose meprobmte possesses n mechnism. This notion is supported by cute 25 nd chronic 8 pin together, it ppers tht meprobmte is crucil component of the ultr-low dose codeine combintion nlgesic. Meprobmte s mechnism of nxiolytic ction is relted to its A receptors.9,10 Therefore it ws nticipted tht Stilpne would chieve fr nxiety score of 0 16 is interpreted s mild nxiety. It is thus conceivble tht these ptients experienced no nxiety t ll. Furthermore, it is likely tht whtever procedure-relted nxiety ws present, continued to diminish due to dequte nlgesi s well s to the heling pssge of time. Studies ssessing the more informtive. Although there ppered to be greter trend for pruritus in Stilpne treted ptients nd dizziness nd rsh in ptients who tretment groups. It should be noted tht nuse nd vomiting my dd to the subjective experience of pin, nd tht these dverse events were reported in pproximtely 5 10% of ptients required, underscoring the dvntge of reducing the dose of individul components in combintion nlgesics. Assessing physicl dependence nd/or ddiction potentil of low dose, short term use of trmdol, codeine or meprobmte ws beyond the scope of this study. Conclusion This study demonstrted tht despite their distinctive compositions nd mechnisms of ction, Stilpne nd Trmcet eligible ptients experiencing moderte to severe cute pin. ptients with coexisting high levels of cute nxiety or co-morbid medicl conditions. Menwhile, the interchngeble use of preopertive nxiety, postopertive nxiety ws reduced or Trmcet, ostensibly becuse the nticiptory fer relted to severity of nxiety experienced by most ptients in ech tretment group prior to the dministrtion of the combintion nlgesics ws mild, which mde ssessing ny subtle chnges Acknowledgements The uthors wish to cknowledge Prof FJ Jcobs, Dr GJ Roode, Dr S Nidoo, Miss M. Kotzè; Miss TL Venter their generous funding. writing this pper The pge number in the footer is not for bibliogrphic referencing

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