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Original ArticleEFFICACY AND SAFETY OF DICLOFENAC SODIUM ANDETORICOXIB IN CONTROLLING POST EXTRACTION DENTAL PAIN –A RANDOMISED OPEN LABEL COMPARATIVE STUDYK.Punnagai, K.Gunasekaran, K.Vijaybabu, I.Glory JosephineABSTRACT:AIM: The aim of this study is to evaluate the efficacyand safety of COX-2 inhibitor Etoricoxib 120mg ODcompared to Diclofenac Sodium 50mg BD in postextraction dental pain.MATERIAL AND METHODS: A total number of 100patients posted for third molar extraction wererecruited for the study. Those who met the inclusioncriteria (n = 51) were randomized into twotreatment groups A & B. Group A received T.Diclofenac Sodium and Group B received T.Etoricoxib. Written Informed consent was obtainedfrom all the patients. On the day of surgery patientswere given the study drugs and visual analog scales(VAS) to assess the pain intensity for 5 days.Baseline pain intensity immediately after surgeryand at 8hrs was recorded on the day of surgery. Theywere asked to report any adverse events over phoneduring the study period. On day 5 the completedforms were collected and evaluated statisticallyusing one way analysis of variance.RESULTS: The statistical analysis of pain intensityusing VAS showed that 78% of patients showedsevere baseline pain intensity and at the end of 8hours on the first day of surgery, Diclofenac groupshowed 27% reduction in pain intensity and 39%reduction in Etoricoxib group (P value < 0.05). Onday 5 pain reduction was 97% and 100% inDiclofenac and Etoricoxib group respectively. Globalassessment and safety assessment showed bettergastrointestinal profile for the Etoricoxib thanDiclofenac sodium. No major adverse effects werereported in the two study groups.CONCLUSION: Present study proves that Etoricoxibhas a rapid onset and prolonged pain relief andstatistically significant analgesic effect in theimmediate postoperative period of 8 hrs incomparison to Diclofenac sodium. The traditionaltime tested analgesic Diclofenac sodium 50mg b.dand newer Etoricoxib 120mg are equally effective inpost extraction dental pain. Safety Profile especiallyGIT toxicity was comparatively better for Etoricoxibthan Diclofenac sodium during the study period.Key words: Etoricoxib, diclofenac sodium, visualanalog scale, pain assessment, safetyINTRODUCTIONThe surgical extraction of impacted third molarteeth is a clinically validated, reliable model for acutepain and evaluating the efficacy of analgesics.Patients recruited for this procedure are young,healthy, degree of interpatient variation is less andpatients are naive of previous pain experiences. Thissurgical procedure is clean, uniform, not lifethreatening, causes predictable moderate to severe1pain, with anxiety.Pharmacological management of pain involves theadministration of medications which include: opioidanalgesics, non steroidal anti inflammatory drugs,local anesthetics, glucocorticoids and alpha 2agonists. We are still in constant search of an idealanalgesic drug which alleviates pain, anxietyeffectively and facilitates wound healing withoutundesirable side effects like gastritis, bleeding,sedation and hypersensitivity reactions.Non steroidal anti inflammatory drugs (NSAIDs) arecommonly used drugs for the control of2postoperative pain of moderate to severe intensity.The mechanism of action of NSAIDs is inhibition ofcyclooxygenase-1 (COX-1) and cyclooxygenase-2(COX-2) enzymes and thereby preventing synthesisof prostaglandins. Prostaglandins are one of themajor mediators of pain and inflammationperipherally. COX-1 is protective for gastric mucosa,3platelet action and kidney function. Inhibition ofCOX-1 results in gastrointestinal toxicity and pepticInternational Journal of Basic Medical Science - April 2010, Vol : 1, Issue : 1 151

www.ijbms.comK. Punnagai, et al, Diclofenac Sodium and Etoricoxibulcer. Cox-2 is expressed in only a few specializedtissues like brain and kidney. It is induced duringinflammation and plays important physiological rolesin tissue repair, reproduction and renal function. Thisenzyme is particularly not involved in mucusproduction in stomach. COX -2 inhibitors preventinflammation and sensitization of peripheralnociceptors. In addition they might be safe with4significantly lower incidences of gastric injury.Pain intensity is assessed using pictorial andnumerical ten point Visual Analog Scale (VAS). It isdesigned to present to the patient a rating scalewith minimum constraints. It is simple, quick toscore and avoids imprecise descriptive terms. VASscores during treatment and baseline show aGaussian distribution allowing for the use ofparametric statistical analysis. This scale is widely5applied in studies on dental pain .Diclofenac sodium is a time tested commonly usedNSAID used in painful conditions including acutepostoperative pain. The selection of Diclofenac Sodiumis based on the previous studies, as it is proved to offer6, 7a good combination of efficacy and tolerance.The selection of Etoricoxib is to substantiate itsanalgesic efficacy and safety profile in a short termtreatment of 5 days in controlling postoperative painin Indian population. Pharmacokinetic profile ofEtoricoxib compared to diclofenac sodium isfavourable with rapid absorption and goodbioavailability. Time to peak plasma concentration isquick with elimination half life of 22 hrs in healthyhuman volunteers with once daily dosing. It is aneffective analgesic with good tolerability. Studies onhealthy human beings have demonstrated thatEtoricoxib does not interfere with platelet8, 9aggregation.The primary objective and aim of the present study isto compare the analgesic efficacy and safety of Cox-2 inhibitor Tab. Etoricoxib 120mg once a day withtraditional NSAID Tab. Diclofenac sodium 50mgtwice a day in controlling post extraction dental painin patients undergoing surgery for impacted thirdmolar tooth. The tool used to measure the painintensity is Visual analog scale.MATERIALS AND METHODSThe study was conducted among 51 patients withone or more impacted third molar teeth posted forextraction at the oral surgery department of theDental College, Sri Ramachandra Medical Collegeand Research Institute, Chennai.The institutional Ethics Committee approved thestudy protocol, informed consent form and the casereport form. The study was a randomized, openlabel,comparative, single centre study. Duration ofthe study period is 5 days with either one of thestudy drug. Inclusion criteria included both genderaged from 18-60 years, who were posted forsurgical extraction of impacted third molar tooth,partially or fully impacted or in germinal phase and allwere in good general health, as established byphysical, clinical examination and laboratoryinvestigations. Subjects with hypersensitivity toNSAIDs, infective carries, peptic ulcer,cardiovascular abnormalities, diabetes mellitus,hypertension, bronchial asthma, pregnant, lactatingwomen and subjects who had NSAIDs from two daysbefore extraction of teeth were excluded from the study.The preoperative interviews, the supply of the studymedications and visual analog scales recordings anddischarge instructions were dealt by an independentobserver. Patients who met the inclusion criteriawere consequently randomized using a computergenerated list using random allocation software,version 1.0 in to two groups A and B.Group A patients were given T. Diclofenac Sodiumth50mg 12 hourly and Group B were provided with T.Etoricoxib 120mg once a day daily. All drugs wereprescribed for a period of five days immediately aftercompletion of surgery and continued until sutureremoval on day 5. Both the groups receivedp o s t o p e r a t i v e p r o p h y l a c t i c a n t i b i o t i c sCap.Amoxicillin 1g every 12h for 5 days.All the impacted molars are of equal surgicaldifficulty and were extracted under local Anesthesiawith Lignocaine by the qualified oral surgeons of thestudy site. Intravenous sedation was never used.After undergoing extraction surgery, patients weresupplied with a course of their study analgesic withinstructions in the recovery room and were advised152International Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3

K. Punnagai, et al, Diclofenac Sodium and Etoricoxib www.ijbms.comto take the first dose of the medication immediatelyafter surgery. Rescue medication wasT.Paracetamol 500mg was provided to the patientsif the pain relief is not satisfactory with the studydrugs on the first day. Patients were discharged onthe day of surgery after 8 hour observation period.All patients were provided using a 10 point Visualanalog scale in which they were instructed to recordpain intensity over 5 consecutive days at the sametime from days 1-5, starting from the day of surgery.Pain intensity was recorded immediately aftersurgery using VAS and 8 hrs after surgery anddischarged. The overall effect of the drug (globalassessment of the study medication) on pain andside effects which was assessed by the patients atthe end of the trial (fifth day) on a categorical scalewith the following categories: 1 – Poor, 2 – Fair, 3 –Good, 4 – Excellent. Patients were advised to reportany adverse event immediately over the phone to theindependent observer.On the fifth day of extraction, drug compliance wasassessed by counting the remaining tablets.Patients were enquired of any adverse event andthey underwent physical examination. Globalassessment of the study medications using acategorical scale was recorded from the patients.Visual analog scales were collected back Parametersassessed were Mean pain scores using 10 pointVAS, global assessment of study medications andincidence of adverse effects.One way Analysis of variance test was used tocompare the pain intensity (VAS) between the twotreatment groups. Intergroup comparison was doneusing TUKEY'S HSD method. The pain intensity atbaseline was included as a covariate in the analysis ofpain intensity. The P values below 0.05 wereconsidered to be statistically significant. Noadjustment was performed for pair wisecomparisons between treatments.RESULTSThe baseline demographic characteristics weresimilar among groups. Overall 47 % (24/51) ofpatients were females and 53 % (27/51) weremales. Approximately 78% of patients (38/51)reported severe pain after surgery and 6% (3/51)reported modedrate pain (Table 1). The use ofintraoperative anaesthesia was limited toepinephrine administered with lignocainehydrochloride (Table 1).The primary efficacy measure was pain intensity. Theoverall analgesic efficacy of the study drugs over theperiod of 8 hrs, 24hrs, day 3, day 4 & day 5, weremeasured by reduction in pain intensity using visualanalog scale.On end of surgery at 1hr the baseline mean painintensity score ± SD for the Diclofenac sodiumgroup was 8.76 ± 1.48 and Etoricoxib 120mg groupwas 8.64 ± 1.58. At the end of 8 hours of surgery,Diclofenac sodium group showed 6.36 ± 1.63(CI=8.15-9.37) with 27% reduction in the painintensity. In case of Etoricoxib group pain score was5.22 ± 2.01 (CI=7.99-9.29) with 39% reduction inpain intensity which was statistically significant.On day 2 pain score was 3.64 ± 2.31 (CI=5.69-7.03) with 58% reduction in pain intensity inDiclofenac group, and 3.8 ± 1.78 (CI=4.41-6.07)with 56% reduced pain intensity in Etoricoxib group.On day 3 pain score was 1.64 ± 1.73 (CI= 2.69-4.59) with 81% reduction in pain intensity inDiclofenac group, and 1.40 ± 1.47 (CI=0.79-2.01)with 83% reduced pain intensity in Etoricoxib group.On day 4 in Diclofenac group pain score was 0.32 ±0.63 with 96% reduction in pain intensity, and inEtoricoxib group the pain score was 0.28 ± 0.61with 96% reduced pain intensity respectively.On day 5 the pain score was 0.28 ± 0.61 with 96%reduction in pain intensity in Diclofenac sodiumgroup and 0.02 ± 0.20 with 100% reduced painintensity in Etoricoxib group. Mean daily pain scoresin each treatment group over the period of 1 hr ofday 1 to the day 5 as well as p values are shown inTable 2.This analysis including baseline pain intensity as acovariate, shows that the pain intensity is notstatistically significant different between groupsexcept for significant pain relief with Etoricoxib120mg (8hrs) (p value < 0.05). There was noevidence of any statistical difference between drugsfor relief of pain on day 2 to day 5. (Fig 1)International Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3 153

www.ijbms.comK. Punnagai, et al, Diclofenac Sodium and EtoricoxibThe incidence of side effects, especially theepigastric pain and nausea, were significantly higherwith treatment of diclofenac sodium than Etoricoxibin appropriate doses. No serious adverse eventsoccurred. One woman reported of vomiting after 6hours of taking diclofenac sodium as shown in Table 3.The overall effect of the drug (global assessment ofthe study medication) on pain and side effects whichwas assessed by the patients at the end of the trial(day 5) on a categorical scale. All drugs wereassessed as good and excellent.Sex n (%)FemaleCharacteristicsT. Diclofenacsodium n=26T.Etoricoxibn=2514 (53%) 10 (40%) 24 (47%)Male 12 (47%) 15 (60%) 27 (53%)Age, yr(mean ± SEM) 32.5 (1.72) 30 (1.88) 31.3 (1.80)Weight (kg) 60±10 62±11 61±10.5Length of surgery (minutes) 28±12 31±13 29.5±12.5Local anaesthesia (ml) 4±1 4±1 4±1Baseline pain intensity n (%) Severe:(VAS>8) 15 (58) 23 (92) 38 (78%)Moderate: (VAS>5) 2 (8) 1 (4) 3 (6%)Table 1. Baseline Characteristics Between GroupsTotaln=51Study PeriodDiclofenac Sodium 50MG BD(mean ± SD)Etoricoxib 120MGsEM sEM P VALUEOD (mean ± SD)DAY 1-1 hr 8.76 ± 1.48 0.29 8.64 ± 1.58 0.31 .748DAY 1-8 hrs 6.36 ± 1.63 0.32 5.22 ± 2.01 0.40 .000DAY 2 3.64 ± 2.31 0.45 3.8 ± 1.78 0.36 .474DAY 3 1.64 ± 1.73 0.35 1.40 ± 1.47 0.29 .276DAY 4 0.32 ± 0.63 0.13 0.28 ± 0.61 0.12 .367DAY 5 0.28 ± 0.61 0.12 0.02 ± 0.20 0.04 .154Table 2. Mean Pain Scores ± Sd Using Visual Analog ScaleFig 1. MEAN VISUAL ANALOG SCORE FOR PAIN INTENSITYADVERSE EVENTSDICLOFENACSODIUM n=26ETORICOXIBn=25TOTAL n=51NAUSEA, VOMITING 5 1 6POSTOPERATIVE BLEEDING 5 2 7DIZZINESS 3 2 5EPIGASTRIC PAIN 5 0 5HYPERSENSITIVITY REACTIONS 1 1 2OTHERS (edema, cough) 1 2 3TOTAL NO. ADVERSE EFFECTS 20 8 28Table 3. Adverse events profile of study drugs154International Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3

K. Punnagai, et al, Diclofenac Sodium and Etoricoxib www.ijbms.comDISCUSSIONIn a national survey conducted in USA by JeffreyL.Apfelbaum et al.and published in 2003, it wasreported that approximately 80% of all patientsexperienced acute pain after surgery. Most of theinpatients and outpatients had moderate, severeand extreme pain. Ambulatory patients felt morepain after discharge than when they are in the10hospital.With increasing attention being given to successfulpostoperative pain management in the hospitalsetting, development of newer analgesics withpotency and fewer adverse effects, and use ofbalanced analgesia plays a prominent role.The role of the COX-2 inhibitors in the managementof other conditions such as osteoarthritis andrheumatoid arthritis has been widely discussed.However, their role in the treatment ofpostoperative dental pain which is a reliable methodfor comparing analgesics has been evaluated to alesser extent in south Indian population. In thepresent clinical study, approximately 78% reportedsevere baseline pain intensity following surgicalremoval of an impacted third molar tooth using visualanalog scale. The overall analgesic efficacy andanalgesia during the acute postoperative period (8hrs after surgery) and duration of analgesic effectwere evaluated and compared between the studydrugs (T.Etoricoxib and T.Diclofenac sodium).At the end of 8 hrs of postoperative period, theanalgesia produced by T.Etoricoxib was statisticallysignificant to the analgesia produced by T.Diclofenacsodium (P value < 0.05). This proves the quick onsetof peak analgesic action of Etoricoxib compared toDiclofenac sodium. This result can be extrapolated ina clinical setting to control the acute pain effectivelywith Etoricoxib on the day of surgery. On the first dayof postoperative period the pain relief was almostsimilar in both groups showing the prolonged actionof Etoricoxib in a single daily dose and improvedcompliance with the use of this drug.However, on the fourth day of postoperative period ofour study the pain relief was almost complete andsimilar in the both treatment groups. So the overallanalgesic efficacy of the single dose of COX-2inhibitor Etoricoxib 120mg was found to be equal inefficacy to nonselective NSAID, Diclofenac sodiumwhich was given in two divided doses. Patients wereoverall satisfied with the analgesic efficacy of boththe study drugs evaluated by global assessmentscale.The traditional post-surgical analgesia with nonselectiveNSAIDs and opioids are associated withseveral side effects such as post-operative bleeding,gastrointestinal problems, nausea, andconstipation. The incidence of GI perforations,ulcers, bleeding with Etoricoxib is far less than halfthat associated with older NSAIDs in a combinedanalysis of data from ten clinical trials. COX-2inhibitors are especially useful in patients with a highrisk of upper gastrointestinal bleeding or with a11history of peptic ulcer.Safety assessment showed that both the drugsused in the study were generally well tolerated.No serious adverse event was reported amongp a t i e n t s i n a l l t r e a t m e n t g r o u p s .Gastrointestinal side effects like epigastric painand nausea were greater in the diclofenac sodiumgroup compared to Etoricoxib. No episodes ofsevere gastritis and vomiting were reported inEtoricoxib group confirming the advantage ofEtoricoxib over Diclofenac sodium. They do nothave any significant effect on platelet function as12, 13COX-1 inhibitors. The use of COX-2 inhibitorshas been possibly reported to have increased thecardiovascular and cerebrovascular adverse14effects.According to the European Medicines Agency(EMEA) when COX-2 inhibitors are prescribed inaccordance with contraindications and precautions,the balance of benefit and risk remains positive in15target patient population. In India manypreparations of Etoricoxib is approved for use foracute pain conditions in the lowest effective dose for16a limited time in adults.In the present study being a short term acute painstudy, no reports of such serious intolerance andadverse events occurred in the entire treatmentgroups with Etoricoxib and Diclofenac sodium. ToInternational Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3 155

www.ijbms.comK. Punnagai, et al, Diclofenac Sodium and Etoricoxibprove and substantiate the safety and efficacy ofEtoricoxib in painful conditions many more clinicaltrials and studies with good sample size and soundmethodologies are needed in Indian population.CONCLUSIONIn this clinical study, Diclofenac sodium 50mg BD andEtoricoxib 120mg OD were overall similar inanalgesic efficacy and safety. While both NSAIDsprovide a better pain relief in patients followingimpacted third molar extractions, Etoricoxib has arapid onset of pain relief and prolonged duration ofaction in comparison to diclofenac sodium in theimmediate postoperative period and can beespecially useful in individuals with gastritis and acidpeptic disease. Diclofenac sodium is preferably costeffective. Nevertheless, the risk vs. benefit andother cardiovascular, renal adverse effects must beconsidered while selecting particular NSAIDs for thetreatment of dental pain.ACKNOWLEDGEMENTWe sincerely thank the Professor and HOD of thed e p a r t m e n t o f P h a r m a c o l o g y, S R M CDr.S.Parvathavarthini for her guidance in thisstudy. Our thanks to the Prof and HOD Dr.Raveendran, of the department of Oral Surgery,SRMC Dental College for his cooperation.DECLARATIONS:No funding for the paperNo conflicts of Interest.REFERENCES1.2.3.Forbes JA. Oral surgery, advances in painresearch and therapy: the design ofanalgesic clinical trials. Max MB, PortenoyR, Laska EM, eds. New York: Raven Press,Ltd, 1991:347-74.Mehlisch DR, Markenson J, Schnitzer TJ. Theefficacy of nonsteroidal anti-inflammatory drugsfor acute pain. Cancer Control 1999; 6:5-9.Kaplan-machlis B, Klostermeyer BS. Thecyclooxygenase-2 inhibitors: safety and4.5.6.7.8.9.10.11.effectiveness. Ann Pharmacother 1999;33:979-88.Wolfe MM, Lichtenstein DR, Singh G.Gastrointestinal toxicity of nonsteroidalantiinflammatory drugs. N Engl J Med 1999;340:1888-99.Vickers ER, Cousins MJ, et al. Pain descriptionand severity of chronic Orofacial painconditions. Australian Dental Journal; 1998;43: 403-9. (28) in dissertation.Breivik EK, Pal Barkvoll, Eva Skovlund. Combiningd i c l o f e n a c w i t h a c e t a m i n o p h e n o racetaminophen-codeine after Oral surgery: Arandomized, double-blind single-dose study. ClinPharmacol Ther 1999; 66: 625-35.Estelle – Martinez V, et al. Analgesic efficacy ofdiclofenac sodium versus Ibuprofen followingsurgical extraction of impacted lower thirdmolars. Med Oral Pathol Oral Cir Buccal 2004;9: 444-53.Hunt RH, Harper S, Watson DJ, et al. Thegastrointestinal safety of the COX-2 selectiveinhibitor etoricoxib assessed by bothe n d o s c o p y a n d a n a l y s i s o f u p p e rgastrointestinal events. Am J Gastroenterol2003; 98:1725-33.Dallob A, Hawkey CT, Greenberg H, et al.Characterization of Etoricoxib, a novel,selective COX-2 inhibitor. J Clin Pharmacol2003; 43:573-85.Apfelbaum et al. Postoperative Pain Experience:Results from a National survey suggestPostoperative pain continues to beundermanaged. Anesth Analg 2003; 97:534-40.Moore RA, Derry S, Makinson GT, Mcquay HJ,Tolerability and adverse events in clinical trialsof celecoxib in Osteoarthritis and rheumatoidarthritis: systematic review and meta-analysisof information from company clinical trialreports Arthritis Research & Therapy 2005;7(3):R644-65.156International Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3

K. Punnagai, et al, Diclofenac Sodium and Etoricoxib www.ijbms.com1213.14.Mukherjee D et al., COX-2 inhibitors couldincrease risk of cardio vascular events. ThePharmaceutical Journal 2001; 267: 283.Catella – Lawson F, Reilly MP, Kapoor SC, et al.Cyclooxygenase inhibitors and the Antiplateleteffects of aspirin. N.Engl. J. Med., 2001, 345:1809-1817.Anne Burke, Emer M.Smyth, and GarretA.FitzGerald. Analgesic-Antipyretic Agents. In:Laurence LB, John SL, Keith LP. (Eds) Goodman& Gilman's The Pharmacological Basis ofTherapeutics, 11th ed. NY: McGraw Hill; 2005:pp 684-85.15.16.European Medicines Agency, 2008. Questionsand Answers on the Review of EtoricoxibcontainingMedicines. 2008; Doc. Ref.EMEA/329177/2008.Regional Pharmacovigilance Centre (South).Selective COX-2 inhibitors: current status.Drug Alert. 2005; 1(1): 1-4Authors :1.K. Punnagai,Assistant Professor of PharmacologySRMC, Chennai.K. Vijaybabu,Assistant Professor of PharmacologyVMKVMC, Salem.I. Glory Josephine,Assistant Professor of PharmacologyBalaji Medical College, Chennai.2. K. Gunasekaran,Assistant Professor of Anaesthesiology,Saveetha Medical College, Chennai.International Journal of Basic Medical Science - June 2010, Vol : 1, Issue : 3 157